bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1870: Association of prostaglandin-endoperoxide synthase 2 (PTGS-2) polymorphisms with colorectal cancer risk and immunohistochemical detection of PTGS-2 in Chinese colorectal cancer patients
Authors: Lim Rachel Liyu , Lim Jia Qi , Yip Fong Ee , Niah Weixin , Sandanaraj Edwin , Singh Onkar , Koilan Subramaniyan , Chowbay Balram
Published: August 2012

PTGS-2 is an rate-limiting enzyme that can be induced by several factors including mitogens, cytokines, growth factors and tumor promoters. It catalyzes the formation of Prostaglandin E2 (PGE2) that favors carcinogenic processes. Overexpression of PTGS-2 gene encoding PTGS-2 enzyme was observed in several human malignancies including colorectal cancer. Various functional genetic polymorphisms present in the PTGS-2 gene were shown to influence the expression level of the PTGS-2 protein and affect the individuals’ susceptibility to developing colorectal cancer. Whole gene screening in the healthy local Chinese subjects had identified 26 SNPs, which were tagged by 15 tag SNPs. Among these tag single nucleotide polymorphisms (SNPs), two were found in the 5′ upstream region [−1424 A>G (rs689465), −1329 A>G (rs689466)], five were in the intronic region [IVS1+145A>G (rs11567820), IVS2-22C>G (rs20427), IVS3+36C>T, IVS9+146C>T and IVS9-164G>T], two were in the coding region [306G>C (rs5277) and 1759G>A(rs3218625)], four were in the 3′ untranslated region (UTR) [*427T>C (rs5275), *2267G>T (rs4648302), *2358T>A (rs13306038), *2368_*2369insA] and two were located in the 3′ downstream region [*+2868G>A (rs4648308), *+4038_*4039insTA] of the PTGS-2 gene. This study aimed to investigate the association between fifteen PTGS-2 tag SNPs and one functional SNP [-899G>C (rs20417)] with (1) the risk of developing colorectal cancer and (2) the expression level of PTGS-2 protein in the tumor resections in Chinese colorectal cancer patients (N=90). The genetic association analysis indicated that patients harboring the heterozygous genotype (TC) of *427T>C (rs5275) SNP had a significant reduced risk in colorectal cancer predisposition (codominant model: Odds Ratio (OR)=0.51; 95% Confidence Interval (CI)=0.25-1.03; P=0.033 and overdominant model: OR=0.47; 95% CI=0.24-0.95; P=0.033). However, this SNP was not found to be significantly associated with the PTGS-2 expression in the tumor resections of the patients (N=48). No significant correlation was observed between other investigated tag SNPs with colorectal cancer risk and PTGS-2 protein expression. The findings of this study suggest that *427T>C (rs5275) might be a biomarker for colorectal cancer predisposition in the local Chinese colorectal cancer patients. Further conformational investigations in larger cohort should be performed to validate the findings of the present study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1870. doi:1538-7445.AM2012-1870
Abstract 1888: MM-111, a bispecific HER2 and HER3 antibody, inhibits trastuzumab-resistant tumor cell growth
Authors: Zhang Bo , Nguyen Stephanie , Huhalov Alexandra , Nielsen Ulrik B. , Niyikiza Clet , McDonagh Charlotte F. , Kudla Arthur J. , Onsum Matthew
Published: August 2012

Amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 25% of breast cancers and is associated with increased disease recurrence and poor prognosis. Trastuzumab, a monoclonal antibody targeting HER2, has demonstrated clinical benefit in HER2 over-expressing tumors. However, acquired resistance and disease progression is widely observed in patients treated with trastuzumab. In this experiment our objectives were to dissect the dynamic, molecular mechanisms involved in acquired resistance to trastuzumab and to determine whether MM-111, a novel bispecific antibody fusion protein that specifically targets the HER2/HER3 heterodimer and blocks heregulin binding to HER3, has activity in trastuzumab-resistant tumor cells. BT474 cells were cultured in the presence of trastuzumab and cells were periodically tested for response to trastuzumab and MM-111. Samples were also collected for protein and RNA analyses. Resistance to trastuzumab gradually increased in BT474 cells after four months of exposure to trastuzumab, as measured by a cell proliferation assay. Quantitative flow cytometry analysis showed EGFR, HER2, and HER3 levels on the cell surface of resistant cells were similar to the parental cells. Phospho-protein kinase antibody arrays revealed that signaling pathways associated with the ERK cascade were activated during the development of drug resistance. Western blotting further confirmed that phosphorylation of EGFR, ERK, CREB, c-Jun, and AFT-1 was increased in the resistant cells. Real-time polymerase chain reaction also showed transcript levels of HER ligands, including HRG1α, HRG1α, betacellulin, amphiregulin, epigen, TGFβ, and HB-EGF, dramatically increased in tumor cells that acquired resistance to trastuzumab. Compared to the BT474 parental cells, MM-111 showed a greater inhibition in trastuzumab-resistant cells in a spheroid growth assay. Furthermore, trastuzumab-resistant cells became more sensitive to gefitinib and erlotinib, both EGFR inhibitors. The combination of gefitinib or erlotinib with MM-111 showed greater inhibition than either drug alone. In conclusion, our data suggest that one mechanism by which HER2 overexpressing breast cancer cells develop resistance to trastuzumab is to up-regulate ligand-dependent EGFR and HER3 signaling pathways. The use of MM-111 and EGFR inhibitors may provide an effective therapeutic strategy for the treatment of trastuzumab-resistant cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1888. doi:1538-7445.AM2012-1888
Abstract 1891: NF-κB signaling plays a certain role in apoptosis resistance in 3D-cultured EGFR-mutant lung adenocarcinoma cells
Authors: Sakuma Yuji , Miyagi Yohei
Published: August 2012

It is generally thought that suspended tumor cells show reduced proliferative activity and are more resistant to conventional chemotherapy compared with adherent tumor cells. Two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R + T790M), cultured in suspension, however, undergo apoptosis much more easily than these two cell lines cultured in conventional monolayer dishes, i.e. anchorage dependent conditions, when the kinase activity of EGFR is completely inhibited by treatment with EGFR tyrosine kinase inhibitors (TKIs) regardless of suspension or monolayer culture conditions. These findings indicate that attached EGFR-mutant lung adenocarcinoma cells appear less dependent on constitutive EGFR signaling for survival than detached cells, probably because integrin ligation enhances cell survival in adherent cells. However, the microenvironment of cells in monolayer culture conditions is considerably different from that of cells in vivo. We thus tested whether EGFR-mutated lung adenocarcinoma cells in three dimensional (3D) conditions using Matrigel resist EGFR TKIs-induced apoptosis compared with suspended cells. We uncovered three major findings in this study as follows: 1) both HCC827 cells and H1975 cells cultured in 3D conditions were significantly less sensitive to EGFR TKIs-induced apoptosis than suspended cells. 2) Marked degradation of IαBβ, the inhibitor of NF-κB pathway, was observed only in 3D-cultured EGFR-mutated lung adenocarcinoma cells, resulting in NF-κB signaling activation. 3) TPCA-1, a potent IKKα inhibitor, can enhance the levels of apoptosis in 3D-cultured EGFR-mutant cells treated with EGFR TKIs. These results suggest that combined EGFR and NF-κB inhibition is required to induce apoptosis effectively in EGFR-mutated lung adenocarcinoma cells in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1891. doi:1538-7445.AM2012-1891
Abstract 190: Long noncoding RNA XY11-10-11 regulates proliferation and migration of esophageal adenocarcinoma cells
Authors: Yang Xue , Wu Wenjing , Margolies Nathaniel , Song Jee Hoon , Cheng Yulan , Meltzer Stephen J.
Published: August 2012

Esophageal carcinoma is one of the most common types of cancer, ranked among the top eight causes of cancer death worldwide. The molecular mechanisms underlying esophageal cancer are very complicated and have not yet been completely clarified. In recent years, long noncoding RNAs (lncRNAs) have been shown to play critical regulatory roles in various cancer biology, yet their potential involvement in esophageal cancer is not well understood. Here, we identified a set of lncRNAs that are differentially expressed in esophageal cancer tissues in comparison to the normal tissues using quantitative real-time polymerase chain reaction. A new lncRNA, which we name XY11-10-11, is significanty increased in expression in human esophageal adenocarcinoma tissues and cell lines. XY11-10-11 is an intergenic lncRNA expressed from a locus located on chromosome 14. Importantly, knockdown of XY11-10-11 by siRNA resulted in inhibition of proliferation and migration in esophageal adenocarcinoma cells (EACs). Moreover, patients with high XY11-10-11 expression levels had a relatively poorer prognosis. Our findings indicate that XY11-10-11 may play a significant role in the development or progression of esophageal adenocarcinoma and may be an potential biomarker for diagnosis and therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 190. doi:1538-7445.AM2012-190
Abstract 1901: EGFR and K-Ras mutations and resistance of lung cancers to IGF-1R TKI
Authors: Kim Woo-Young , Prudkin Ludmila , Feng Lei , Kim Edward , Hennessy Bryan , Lee Ju-Seog , Lee J. Jack , Glisson Bonnie , Lippman Scott , Wistuba Ignacio , Hong Waun Ki , Lee Ho-Young
Published: August 2012

Background: Most patients with non-small cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF-1R TKIs. Methods: Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in a NSCLC tissue microarray. We analyzed the antitumor effects of an IGF-1R TKI (PQIP or OSI-906), either alone or in combination with a small-molecular inhibitor (PD98059 or U0126) or with siRNA targeting K-Ras or MAPK/extracellular signal-regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K-Ras mutations. Results: pIGF-1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant (mut) K-Ras, and wild-type (wt) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NSCLC cells with wt EGFR and wt K-Ras but not in those with mutations in these genes. Introduction of mut K-Ras attenuated the effects of IGF-1R TKIs on NSCLC cells expressing wt K-Ras. Conversely, inactivation of MEK restored sensitivity to IGF-TKIs in cells carrying mut K-Ras. Conclusions: The mutation status of both EGFR and K-Ras could be predictive markers of response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF-1R TKIs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1901. doi:1538-7445.AM2012-1901
Abstract 1906: Mechanisms of resistance to EGFR tyrosine kinase inhibitors involving HER-family ligands and receptors
Authors: Iwanaga Kentaro , Sueoka-Aragane Naoko , Sato Akemi , Nakamura Tomomi , Kobayashi Naomi , Sueoka Eisaburo , Kimura Shinya
Published: August 2012

Known mechanisms of acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI), including the second mutation of EGFR, T790M, MET amplification, and HGF overexpression, explain approximately 60% of cases, but the remaining mechanisms have not been clarified. To investigate novel mechanisms of acquired resistance to EGFR-TKI, we examined HER-family ligands and HER-family receptor status in non-small cell lung carcinoma (NSCLC) cell lines (n=13). Cell lines were divided into two groups with respect to EGFR-TKI sensitivity: highly sensitive (HCC827, PC-9, HCC2935, and HCC4006) and resistant (H1395, H1666, H596, H1437, A549, H226B, H1299, H460, H1792). We examined expression levels of eleven HER-family ligands_EGF, TGFβ, amphiregulin (AREG), betacellulin (BTC), HB-EGF, epigen (EPGN), epiregulin (EREG), and neuregulin (NRG) 1, NRG2, NRG3, and NRG4_in these cell lines. NRG2, NRG4, and EPGN were expressed at 39.5-, 31.4-, and 6.5-fold higher levels, respectively, in EGFR-TKI primary resistant NSCLC cell lines than in highly sensitive cell lines, whereas TGFA, EGF, and AREG were expressed at 0.22-, 0.3-, and 0.34-fold lower levels. Phosphorylation of EGFR was elevated in sensitive cell lines compared to resistant cell lines, but HER2-4 receptors did not evidence a difference in phsophorylation. These results suggest that the EGFR pathway is activated in sensitive cell lines, and HER2-4, which binds to EPGN, EREG, NRG2, and NRG4, might be activated in resistant cell lines. We prepared cell lines HCC827GR and HCC827ER, derived from HCC827, which acquired resistance to gefitinib or erlotinib, respectively. We analyzed HER-family ligands and receptors using these cell lines. Compared to parent cells, EPGN, EREG, HB-EGF, TGFA, NRG1, and AREG were up-regulated in HCC827GR. Phosphorylation status of EGFR, HER2, and HER3 was not altered, but that of HER4 was increased in HCC827GR. In HCC827ER, EGFR binding ligands AREG, BTC, and EGF were down-regulated, while phosphorylation of EGFR, HER2, and HRE3 was decreased. However, NRG2 was remarkably elevated and HER4 and its downstream STAT5 were phosphorylated. These results indicate that HER4 and its binding ligands may contribute to acquired resistance to EGFR-TKI. Considering these results, it is possible that the HER4-STAT5 pathway might be common to primary and acquired resistance to EGFR-TKI. We continue to investigate its significance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1906. doi:1538-7445.AM2012-1906
Abstract 1923: The mTOR kinase inhibitor, CC214, preferentially blocks the growth of EGFRvIII-activated glioblastomas
Authors: Gini Beatrice , Guo Deliang , Nathanson David , Shackelford David , Zhu Shaojun , Yang Huijun , Tanaka Kazuhiro , Babic Ivan , Akhavan David , Bonetti Bruno , Mortensen Deborah , Xu Shuichan , Raymon Heather , Chopra Rajesh , Mischel Paul
Published: August 2012

mTOR pathway hyper activation is a common feature in many cancers, including in nearly 90% of Glioblastomas. mTOR exists in two multiprotein complexes, which differ in regulation, function, and response to the allosteric mTOR inhibitor rapamycin. The failure of glioblastomas to clinically respond to rapamycin appears to be mediated both by inability of rapamycin to inhibit mTORC2 signaling, and by failure to fully suppress p4E-BP1, a critical effector of mTORC1. The new generation of mTOR kinase inhibitors (mTORki) has emerged as a new class of targeted cancer therapies capable of blocking mTOR more potently than rapalogs (such as Rapamycin). Here we demonstrate that CC214-1 and CC214-2, mTOR kinase inhibitors, have potent effects on the growth of glioblastoma in vitro and in vivo. Across a panel of GBM cell lines, CC214-1 was significantly more effective at suppressing 4E-BP1 phosphorylation and protein translation, and mTORC2 signaling than rapamycin, resulting in significantly more growth inhibition at equal levels of suppression of S6 phosphorylation. EGFRvIII, the constitutively active EGFR mutant frequently detected in GBMs strongly activates mTORC1 and mTORC2 signaling, potently sensitizing tumors to CC214-1. In contrast, PTEN expression suppressed mTOR signaling and reduced the response to CC214-1. In vivo CC214-2 significantly inhibited mTORC1 and mTORC2 signaling, significantly suppressing tumor growth by 50%. CC214-1 also potently activated autophagy. Addition of chloroquine suppressed autophagy resulting in significant CC214-1-dependent apoptotic cell death. These results demonstrate the potential activity of mTOR kinase inhibitors in GBM, and identify EGFRvIII expression and PTEN loss as molecular determinants of response. These data also suggest that mTOR kinase inhibitors, alone or in combination with autophagy inhibiting agents, are likely to have significant anti-tumor efficacy in GBM patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1923. doi:1538-7445.AM2012-1923
Abstract 1924: The aurora kinase inhibitor CYC3 synergizes with low concentrations of paclitaxel in pancreatic cancer cells in vitro
Authors: Lin Yao , Krippendorff Ben-Fillippo , Bramhall Jo , Bapiro Tashinga , Richards Frances , Jodrell Duncan , Zheleva Daniella
Published: August 2012

CYC3, an Aurora Kinase A specific inhibitor, suppresses the pancreatic cancer cell growth (72h GI50 2.4μM in MiaPaCa-2 cells and 1.95μM in Panc-1 cells), arrest the cells at M phase and induces apoptosis. In order to evaluate CYC3's clinical potential, we employed mathematical models and simulations to look for possible synergistic combinations of CYC3 with paclitaxel in MiaPaCa-2 and Panc-1 cells. We have identified low concentrations of paclitaxel (3nM) and CYC3 is synergistic in inhibiting pancreatic cell growth, achieving similar effects as high concentrations of paclitaxel (30nM). Liquid Chromatography-Mass Spectrometry (LC-MS) analysis shows that CYC3 does not alter the cellular uptake of paclitaxel, supporting a synergistic mechanism at molecular level. In addition, the combination of CYC3 with low concentration of paclitaxel (3nM) displays less myelotoxicity compared to high concentrations of paclitaxel (30nM) in colony formation assay using Colony Forming Unit of Granulocyte and Macrophage (CFU-GM) (60-70% vs 100% inhibition), suggesting a potentially safer but equally efficient application of paclitaxel in patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1924. doi:1538-7445.AM2012-1924
Abstract 1927: Mechanistic characterization of SC144 in colon cancer
Authors: Xu Shili , Oshima Takashi , Grande Fedora , Neamati Nouri , Garofalo Antonio
Published: August 2012

Recently, we have designed and synthesized a novel quinoxalinhydrazide, SC144, that showed cytotoxicity in a panel of human cancer cell lines. Here, we found that SC144 exhibited anticancer activity in a panel of drug-sensitive and drug-resistant colon cancer cell lines. To study the molecular anticancer mechanism of SC144, we further found that it arrested cell cycle progression and induced apoptosis in colon cancer cells, which is associated with the decrease in cyclin D1 expression and the activation of the p38/IL-24/Fas pathway. Additionally, in surgical specimens from 202 colorectal patients, Cyclin D1 expression was significantly higher and IL-24 expression was significantly lower in cancer tissue than in adjacent normal mucosa, and there was a significant correlation between IL-24 level in colorectal cancer tissue and the survival rate of patients after cytoreductive surgery (P = 0.007). This clinical evidence further supports that SC144 is a promising therapeutic agent for colon cancer therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1927. doi:1538-7445.AM2012-1927
Abstract 193: Prognostic impact of miR-146 polymorphism in patients with resected colorectal cancer
Authors: Kang Byung Woog , Lee Soo Jung , Moon Joon Ho , Chae Yee Soo , Sohn Sang Kyun , Kim Jong Gwang
Published: August 2012

Background: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. The rs2910164 is a C to G polymorphism located within the sequence of miR-164a precursor, which leads to a change from a C:U pair to a G:U mismatch in its stem region. Recent evidence suggested that the rs2910164 SNP in miR-146a was associated with development of familial breast and ovarian cancers, and prostatic cancer. The aim of this study was to investigate the association between this genetic variant and prognosis of colorectal cancer (CRC) operated curatively. Methods: A total of 343 CRC patients underwent curative surgery were consecutively enrolled between 2004 and 2006. DNA was extracted from fresh frozen normal tissue and miR-146 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: With a median follow up of 42.3 months, the combined GG+CG genotype demonstrated a better survival outcome compared with the CC genotype in a Kaplan-Meier survival analysis. Multivariate analysis showed that the G allele of miR-146 was associated with better progression-free and disease-specific survival as a dominant model adjusted to age, sex, histologic grade and stage [HR=0.54 and 0.49; P = 0.018 and 0.025, respectively]. Moreover, the tumors containing the G allele were histologically associated with more prominent lymphovascular invasion. Conclusions: Our results suggest that miR-146 polymorphism is possible prognostic marker in operated CRC patients in Korean.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 193. doi:1538-7445.AM2012-193
Abstract 1930: Inhibition of glioblastoma cell growth with the isoprenoids perillyl alcohol, farnesol, and geraniol
Authors: Dickerson Lindsy , Jain Aditi , Crowell Pamela L. , Lai James C. K. , Bhushan Alok
Published: August 2012

The naturally occurring isoprenoid perillyl alcohol has chemotherapeutic activity toward many solid tumor types. Early phase human clinical trials have shown low toxicity but only limited efficacy. In glioblastoma, perillyl alcohol has antitumor activity toward cultured cells and has shown some survival benefit in a Phase I/II clinical trial. More potent compounds are needed in order to make more significant impacts on patient survival from glioblastoma and other chemoresistant cancers. Isoprenoids may be especially useful in glioblastoma given their lipophilic nature and potential to cross the blood-brain barrier. Here, we compared the chemotherapeutic effects of perillyl alcohol with the related isoprenoids farnesol and geraniol on cell survival in cultured U87 human glioblastoma cells. Cells were treated for 72 h with isoprenoids, and cell survival was measured by the MTT assay. In U87 cells, each of the isoprenoids exhibited a dose-dependent effect on cell survival in the range of 0-2 mM. The relative potency was farnesol>perillyl alcohol>geraniol, with 52%, 38% and 23% inhibition at 1500 uM, respectively. We then tested the effects of isoprenoids on mitogenic signaling via ERK, phosphoERK, AKT and phosphAKT Western blots in U87 cells. Farnesol decreased phosphoERK at doses as low as 50 uM, whereas perillyl alcohol and geraniol had no effect. None of the isoprenoids affected phosphoAKT, total AKT, or total ERK. Together, these data suggest that farnesol may be a more effective agent than perillyl alcohol in the chemotherapy of glioblastoma, and its effects may be due in part to inhibition of ERK phosphorylation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1930. doi:1538-7445.AM2012-1930
Abstract 1935: Potent anti-tumor effects of TIC10 require Foxo3a and TRAIL gene upregulation
Authors: Allen Joshua E. , Krigsfeld Gabriel , Patel Akshal S. , Wu Gen Sheng , Dicker David T. , El-Deiry Wafik S.
Published: August 2012

TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that induces tumor-selective apoptosis and is currently being tested in clinical trials as an anti-tumor agent. Despite promising preclinical activity, recombinant human TRAIL suffers from efficacy-limiting properties such as short serum half-life, stability, cost, and limitations in delivery, e.g. to the central nervous system. We hypothesized that induction of the human TRAIL gene by small molecules may overcome these limitations of TRAIL-based protein therapy. A cell-based luciferase reporter screen using the human TRAIL promoter identified TIC10 as a p53-independent small molecule inducer of the TRAIL gene. TIC10 induces TRAIL on the surface of normal and tumor cells, in sera of non-tumor-bearing mice, and throughout the tumor microenvironment. Co-culture experiments suggest that TRAIL upregulation by normal cells can contribute to the anti-tumor response of TIC10 through a TRAIL-mediated bystander effect. TIC10-induced TRAIL causes tumor-specific and TRAIL-mediated cell death as indicated by inhibition of cytotoxic effects following TRAIL gene knockdown in vitro and in vivo. Expression profiling of TIC10-induced transcriptional changes revealed altered expression levels of Foxo3a target genes, including DR5. We found that TIC10 causes the nuclear translocation of Foxo3a, but not Foxo1, to upregulate TRAIL gene transcription as determined by chromatin-immunoprecipitation assays. Western blot analysis indicated that TIC10 potently inhibits the phosphorylation of Foxo3a at Ser253 and Ser294 that normally docks the transcription factor to 14-3-3 proteins in the cytosol. Dual inhibition of Akt and ERK by TIC10, by other individual small molecule kinase inhibitors in combination or targeted siRNA inhibited the phosphorylation of these critical serine residues and synergistically induced Foxo3a-dependent TRAIL and TRAIL-mediated cell death. TIC10 is a promising first-in-class anti-tumor agent with a broad range of anti-tumor effects in preclinical animal models including othrotopic GBM, immunocompetent lymphoma, xenografted colon, lung, or breast cancers, and exhibits synergy with taxanes as well as bevacizumab among other agents. TIC10 appears to have no measurable toxic effects in mice including evaluation of serum chemistries, liver function studies, LDH, tissue histology, weight of the animals or behavioral changes. We are pursuing the clinical translation of these important findings that indicate a favorable and wide therapeutic index for a novel anti-tumor agent.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1935. doi:1538-7445.AM2012-1935
Abstract 1973: Falcarindiol induces colorectal cancer cell death through activation of ER stress
Authors: Jin Hongri
Published: August 2012

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Current treatment of this cancer generally employs surgical resection combined with chemotherapy using cytotoxic drugs and radiation therapy. Because this therapy is only moderately successful for late stage cancers, novel approaches to the treatment of colorectal cancer are required. Falcarindiol is a natural polyyne from medicinal plant Oplopanax horridus that has been widely used by indigenous people for a variety of diseases. We show that Falcarindiol can selectively kill colon cancer cells but not the normal colon cells. We further show that the observed cell death is mediated through the induction of Endoplasmic Reticulum (ER) stress. We further show that inhibition of ER stress significantly block Falcarindiol-induced colon cancer cell death while knockdown of GRP78, which sensitizes cells to ER stress induced cell death, significantly enhances Falcarindiol-induced cell killing. Interestingly, we find that Falcarindiol exhibits synergistic anticancer activity with 5-FU, a chemotherapeutic drug for colon cancer. These results suggest that Falcarindiol is potentially a valuable candidate that can be used to in the treatment of colon cancer either alone or in combination with current anti-colon cancer agent such as 5-FU. Key words: Falcarindiol; Colon cancer; ER Stress; Cell death.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1973. doi:1538-7445.AM2012-1973
Abstract 1974: Growth inhibition and antitumor activity of chikusetsusaponin IVa methyl ester, an oleanane-type triterpenoid from the root of Acyranthes japonica, in HCT 116 human colon cancer cells
Authors: Chung Hwa Jin , Cho Lan , Park Hyen Joo , Kim Gi Dae , Son Kyun Ho , Pyee Yuna , Song Jayoung , Kim Yeong Shik , Lee Sang Kook
Published: August 2012

Chikusetsusaponin IVa methyl ester (CSME) is an oleanane-type triterpenoid isolated from the root of Acyranthes japonica (Amaranthaceae). In the present study, the growth inhibition and antitumor activity of CSME were investigated in cultured human colon cancer cell HCT 116. CSME inhibited the proliferation of cancer cells with an IC50 value of 22.4 μM. Flow cytometric analysis indicated that CSME markedly induced the accumulation of cells in the G0/G1 phase and the increase of cell population in sub-G1 phase. G0/G1 cell cycle arrest by CSME was associated with the down-regulation of the expression of cyclin D1, cyclin A, CDK4, CDK2, c-myc and Rb phosphorylation. The increase of sub-G1 peak by CSME was closely correlated with the induction of apoptosis, which was evidenced by the induction of cleaved poly-(ADP ribose) polymerase, activation of caspases, and suppression of Bid and Bcl-2 expression. Treatment of CSME (0.25, 1.0, or 3.0 mg/kg, i.p) also effectively suppressed tumor growth in the HCT 116 implanted xenograft nude mouse model without any overt toxicity. Taken together, these findings suggest that CSME might be a potential candidate for the development of cancer chemotherapeutic agents derived from natural products. (Acknowledgement; this study was supported by a grant Studies on the Identification of the Efficacy of Biologically Active Components from Oriental Herbal Medicines from the Korea Food and Drug Administration (2010)).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1974. doi:1538-7445.AM2012-1974
Abstract 1975: The mitochondrial pathway in baicalein and wogonin-induced apoptosis in human colorectal cancer cells
Authors: Wang Chong-Zhi , Somogyi Jacqueline , Yuan Chun-Su
Published: August 2012

Treating colorectal cancer patients commonly involves several conventional modalities, including surgery, radiation, and chemotherapy. The complexity of colorectal cancer, however, requires additional alternatives to improve the therapeutic efficacy of conventional treatment and the quality of life of cancer patients. Medicinal botanicals have recently gained attention as additions to colorectal cancer management. Numerous effective anticancer drugs have been developed from botanicals, and identifying new herbal sources for ideal chemoprevention remains essential to advance the treatment of colorectal cancer. Scutellaria baicalensis extract (SbE) has chemopreventive effects on several cancers. Baicalin, a major constituent of SbE, also may have the negative effect of decreasing the anti-tumor potential of SbE. In this study, we prepared a baicalin knockout fraction (BKF) of SbE and evaluated its antiproliferative activity and mechanism of action. The constituents of BKF, baicalin fraction (BF), and SbE were quantified by HPLC. We then used an MTS assay to determine the effects of BKF, BF, SbE, and the representative flavonoids on the proliferation of human colorectal cancer cells (HCT-116 and HT-29). Cell cycle, cyclin A expression and cell apoptosis were assayed by flow cytometry. Apoptosis-related gene expression was visualized by quantitative real-time polymerase chain reaction (PCR), and mitochondrial membrane potential was estimated after staining with JC-1. HPLC analysis showed that BKF contained baicalein and wogonin; BF contained only baicalin. SbE had little antiproliferative effect on cancer cells, even increasing cancer cell growth at certain concentrations. BF increased cancer cell growth. BKF showed potent antiproliferative effects on cancer cells. BKF arrested cells in the S and G2/M phases, increased expression of cyclin A, and significantly induced cell apoptosis. Multiple genes in the mitochondrial pathway were involved in BKF-induced apoptosis, and subsequent cellular functional analysis validated the pathway. These results suggest that knocking out baicalin from SbE produces a BKF that significantly inhibits the growth of colorectal cancer cells. The active anticancer compounds in SbE are flavonoid aglycons, baicalein and wogonin, and the mitochondrial apoptotic pathway is part of baicalein and wogonin-induced apoptosis. (This work was supported in part by the NIH/NCCAM grants AT004418 and AT005362).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1975. doi:1538-7445.AM2012-1975
Abstract 1985: Omega-3 polyunsaturated fatty acids induce cell cytotoxicity through apoptosis and autophgy in brain cancer in vitro and in vivo
Authors: Oh Hye-rim , Jing Kaipeng , Shin Soyeon , Kim Nayeong , Jeong Soyeon , Cho Eun-ah , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Han Jeong-su , Park Jong-Il , Kweon Gi-Ryang , Park Seung-Kiel , Yoon Wan-Hee , Hwang Byung-Doo , Lim Kyu
Published: August 2012

One of the most common and biologically aggressive of malignant astrocytic gliomas is glioblastoma (GBM). Studies have revealed a significant role of phosphatidylinositol-3-OH kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling activation during GBM development. Omega-3 polyunsaturated fatty acids (≥3-PUFAs) have been shown to inhibit several cancer cells growth such as breast cancer cells. Here, we examined the anticancer effect of α3-PUFAs in D54 malignant glioma (D54MG) cells. We show that docosahexaenoic acid (DHA), a α3-PUFA, induced apoptosis in D54MG cells, as confirmed by the formation of cleaved PARP, TUNEL assay and cytofluorometric analysis. DHA-treated D54MG cells also showed a significant increase in autophagic activity as revealed by LC3-II elevation, autophagic vesicles formation and autophagy flux assays, suggeting that both apoptosis and autophagy contribute to the DHA-induced tumor cell death. The DHA-induced cell death in D54MG cells was accompained by the activation of AMPK and decrease in the Akt phosphorylation. DHA also decreased the activity of mTOR and the level of its downstream molecule 4EBP as analyzed by the Western blot assay. DHA-induced apoptosis and autophagy were partially blocked by transient overexpression of Akt, supporting the inhibition of Akt being beneficial to the death of GBM cells. In in vivo studies, the growth of implanted murine GBM cells in Fat-1 transgenic mice, that can produce high levels of α3-PUFA, was significantly inhibited, and the apoptotic index was higher compared with wild type mice. Together, these results suggest that α3-FUFAs induce cell cytotoxicity through apoptosis and autophgy in brain cancer. [This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology(2011-0006232).]

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1985. doi:1538-7445.AM2012-1985
Abstract 1988: Increased expression of eukaryotic protein synthesis initiation factor eIF4G by the daidzein metabolite equol may contribute to breast cancer malignancy
Authors: de la Parra Columba , Otero-Franqui Elisa , Dharmawardhane Suranganie
Published: August 2012

The role of dietary soy in cancer has been the subject of intense investigation and is thought to be cancer preventive. However, the beneficial effects of soy on established breast cancer is controversial. We recently demonstrated that dietary daidzein and combined soy isoflavones (genistein, daidzein, and glycitein) promoted breast cancer progression in a nude mouse model by increasing both primary mammary tumor growth and metastasis. Dietary daidzein significantly upregulated cancer promoting molecules including eukaryotic protein synthesis initiation factors (eIF) eIF4G and eIF4E. Herein, using tumors from mice treated orally with daidzein, we show that increased eIF expression is associated with expression of mRNAs with long structured 5′ untranslated regions and internal ribosomal entry sites (IRES) that are sensitive to eIF4E and eIF4G levels. We then tested the hypothesis that daidzein upregulates protein synthesis initiation in breast cancer, but found that daidzein treatment did not affect the levels of eIFs in the same MDA-MB-435 cell line in vitro. Therefore, we tested the effect of equol that is metabolized from daidzein by the gut bacteria in mice and humans. Results show that equol specifically upregulated eIF4G, but not eIF4E, in MDA-MB-435 and MDA-MB-231 human breast cancer cells. Equol treatment also increased gene and protein expression of c-MYC and protein expression of other cell survival and proliferation promoting molecules with IRES sites. The elevated eIF4G in response to equol was not associated with eIF4E in a cap binding co-capture assay. Therefore, upregulation of eIF4G by equol may regulate cap-independent protein synthesis initiation resulting in cancer cell survival, proliferation, and thus, tumor progression. This research was supported by grant numbers US Army/BCRP W81XWH-11-1-0199 to CD, to NIH/NIGMS SC3GM084824 to SD

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1988. doi:1538-7445.AM2012-1988
Abstract 2000: Curcumin prevents human prostate cancer cell invasion by inhibiting of matriptase activity
Authors: Cheng Tai-Shan , Chen Wen-Chi , Lin Ya-Yun , Liao Chia-I , Ko Chun-Jung , Lee Ming-Shyue
Published: August 2012

Curcumin has been shown with potent chemopreventive and antitumor effects on prostate cancer. However, the molecular mechanism how curcumin suppresses prostate cancer cell migration and invasion is not well understood. In this study we showed that curcumin could significantly suppress prostate cancer PC3 cell migration and invasion. Moreover, our data also showed that curcumin was able to suppress EGF- or heregulin-stimulated PC-3 cell invasion, as well as androgen-induced LNCaP cell invasion. Curcumin treatment resulted in not only significant reductions on MMP-9 and MMP-2 activities, but also on activated level of matriptase which is a membrane-bound serine protease and has been proposed to play important roles in tumor invasion and malignancy. Matriptase is synthesized as a full length zymogen, which is rapidly stepped into the maturation process, mature form through a cleavage within the SEA domain to from a latent matriptase. Our data further showed that curcumin can inhibit the latent matriptase formation in the maturation process to affect matriptase activity. Furthermore, the reduction of activated matriptase by curcumin was also partly due to curcumin promoting the shedding of activated matriptase into extracellular environment, but not due to curcumin effect on matriptase gene expression. In addition, we established the stable pools of CWR22Rv1 cells with matriptase overexpression and found that expression of matriptase in CWR22Rv1 cells enhanced their invasive ability. With curcumin treatment, the invasive ability induced by matriptase overexpression was significantly suppressed. In summary, the data indicated that curcumin exhibits a suppressive effect on prostate cancer cell invasion, at least in part by down-regulating matriptase activity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2000. doi:1538-7445.AM2012-2000
Abstract 2004: Ribonucleotide reductase subunit M2 regulates Bcl-2 in human cancer: A potential target for cancer therapy
Authors: Rahman Mohammad Aminur , Amin A.R.M. R. , Koenig Lydia , Nannapaneni Sreenivas , Chen Zhuo G. , Shin Dong M.
Published: August 2012

Ribonucleotide reductase subunit M2 (RRM2) is an essential regulator of DNA synthesis and replication that plays an active role in tumor progression. B-cell lymphoma-2 (Bcl-2) is an anti-apoptotic protein known to promote cell survival. Elevated levels of Bcl-2 have been observed in many cancer types that predict clinical drug resistance. Both RRM2 and Bcl-2 were identified as prognostic factors and indicators of poor patient outcome in several cancers. Therefore, we hypothesized that RRM2 and Bcl-2 proteins might have cooperative functions in cancer progression. We examined correlations of RRM2 and Bcl-2 protein in tissue samples of head and neck squamous cell carcinoma (HNSCC) and non small cell lung cancer (NSCLC) patients by using quantum dots (QDs)-immunofluorescence (IHF) which allows quantification of biomarkers simultaneously in the same tissue slide. A total of 19 cases in each of HNSCC and NSCLC were analyzed. Spearman's correlation coefficient was estimated to measure the relationship between these two proteins. Our data demonstrate highly significant positive correlation between RRM2 and Bcl-2 in both types of cancer (HNSCC: R=0.98, p-value <0.0001; NSCLC: R=0.85, p-value <0.0001). We further investigated the action mechanism of RRM2 and Bcl-2 in cancer progression and explored the role of RRM2 by utilizing siRNA-mediated gene silencing. siRNA knockdown of RRM2 strongly inhibited cell growth and led to apoptosis. Our results demonstrated that overexpression of Bcl-2 protected cells from apoptosis triggered by RRM2 knockdown, indicating that Bcl-2 is a key determinant in controlling intrinsic apoptosis. We further analyzed whether Bcl-2 was regulated by RRM2 at the transcriptional level or at the protein level by post-translational modification. RRM2 most likely regulates Bcl-2 not only at a transcriptional level but also at the post-translational level. We found that RRM2 and Bcl-2 proteins were co-localized and directly interacted. RRM2 depletion significantly increased the rate of Bcl-2 protein degradation, reducing its half-life from ∼9 hours to ∼2 hours. Our study offers a promising approach to Bcl-2 inhibition through targeting RRM2 with siRNA in HNSCC and NSCLC. A protein network-based functional mechanism is defined by which RRM2 regulates Bcl-2-mediated apoptosis. Our novel findings add to the emerging regulatory effects of RRM2 on tumor growth by modulation of Bcl-2. (This work is supported by grants from NIH U01CA151802, P50CA128613 and DOD W81XWH-07-1-0306).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2004. doi:1538-7445.AM2012-2004
Abstract 2216: SUMOylated CPAP contributes to NF-kB activation in cancer cells
Authors: Yang Shu-Ting , Hung Liang-Yi
Published: August 2012

Nuclear factor kappa-B (NF-κB) is a transcription factor which involves in hepatocellular carcinoma (HCC). The development of therapeutic drugs to specifically target NF-κB signaling pathway is imperative to achieve. Centrosomal and P4.1-associated protein (CPAP) is a novel co-activator of NF-κB. The effects of CPAP on NF-κB activation pathway were determined by over-expression and knockdown approaches. CPAP increased the expression of NF-κB target genes by enhancing the transcriptional activaty of NF-κB. Through recruiting more IkappaB kinase beta (IKKα) to the inactivated NF-κB complex, CPAP augmented the phosphorylation of inhibitor of NF-κB (IαBβ) and NF-κB. Chromatin immunoprecipitation assay further showed that CPAP is recruited to IL-8 and ICAM-1 promoter under TNF-α treatment. CPAP was covalently modified by SUMO-1 (small ubiquitin-related modifier-1) protein at the C-terminal region. SUMO-deficient CPAP mutants lost the co-activator activity on NF-κB activation pathway and failed to enter the nucleus upon TNF-α treatment. By immunohistochemistry (IHC) analysis, CPAP was detected in the nucleus of HBV-associated HCC. Activation of NF-κB was synergically augmented by CPAP overexpression in HBx-expressing Hep3B (Hep3BX) and HepG2 (HepG2X) cells lines. SUMOylation of CPAP could modulate the activity of NF-κB, and CPAP may serve as a target for therapeutic purpose in HBV-associated HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2216. doi:1538-7445.AM2012-2216