bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4119: Cytoplasmic location of CXCR4 is correlated to loss of EMT marker and activation of downstream signaling pathway in non-small cell lung cancer
Authors: Wang Yuxiang , Huang Donghai , Fu Hongpeng , Wang Dongsheng , Koenig Lydia , Khuri Fadlo R. , Shin Dong M. , Chen Zhuo (Georgia) 
Published: February 2011

Abstract
Introduction: Although epidermal growth factor receptor (EGFR) targeted therapy initially proved to be effective in some lung cancer patients, emerging resistance to EGFR- tyrosine kinase inhibitor (TKI) became an urgent issue to solve. Some research has shown that cancer cells undergoing epithelial mesenchymal transition (EMT) acquired resistance to EGFR-TKI, though the underlying mechanism remains unknown. Our preliminary study in non-small cell lung cancer (NSCLC) cell lines showed that G-protein coupled chemokine receptor CXCR4 could activate both p-AKT and p-ERK pathways, which have been reported to induce EMT. In this study, we hypothesize that CXCR4 may be an alternative route for cancer cells to bypass EGFR to activate the downstream pathway under an EMT phenotype. Methods: Immunohistochemistry (IHC) was used to detect the expressions of CXCR4, p-AKT, p-ERK, and E-cadherin in 94 clinical NSCLC samples and a weighted index (WI = % expression x intensity score) was used to quantify the expression level of these markers. Western blot was used to detect the expression of CXCR4 and activation of its downstream pathways in NSCLC cell lines. Results: CXCR4 was detected in 98.9% (93/94) of lung cancer samples, however, of greater interest were the 3 distinctive expression patterns for CXCR4 including cytoplasmic, nuclear, and cytoplasmic/nuclear expressions. Since it seems unreasonable to see a transmembrane receptor located in nuclei, we confirmed nuclear localization of CXCR4 by western blot using nuclear extractions from NSCLC cell lines. Furthermore, we evaluated the correlation of different locations of CXCR4 with p-AKT, p-ERK, and E-cadherin by ANOVA statistical analysis. The result showed the expression level of p-AKT and p-ERK are both significantly higher (p=0.004 and p=0.014, respectively) in CXCR4 cytoplasmic and cytoplasmic/nuclear localization groups than those in CXCR4 nuclear localization group. The expression level of E-cadherin in the CXCR4 cytoplasmic and cytoplasmic/nuclear localization groups was also significantly lower (p=0.021) than that in CXCR4 nuclear staining group. Conclusions: Our data suggested that cytoplasmic CXCR4 may contribute to activation of AKT and ERK signaling pathways under EMT, while nuclear localization of CXCR4 may be an inactive form. The functional cytoplasmic CXCR4 may contribute to EGFR-TKI resistance by offering an alternative pathway for tumors to maintain progression. (Supported by grants from NIH R21 CA125062, DOD W81XWH-07-1-0306 Project 5 to ZGC, and GCC Distinguished Scholar Award to ZGC and DMS).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4119.
Abstract 4121: Hyaluronan promotes Rho kinase and PI-3 kinase signaling in head and neck cancer
Authors: Wang Steven J. , Torre Carlos , Xia Weiliang , Bourguignon Lilly YW 
Published: February 2011

Abstract
Objectives: Hyaluronan (HA) is a ligand for the transmembrane receptor CD44, which acts through multiple signaling pathways to influence cellular behavior. The objective of this study was to investigate whether HA and CD44 promote Rho kinase and phosphatidyl inositol-3 (PI-3) kinase mediated oncogenic signaling to alter cisplatin sensitivity and stimulate tumor cell proliferation, migration, and matrix metalloproteinase (MMP) secretion in head and neck squamous cell carcinoma (HNSCC).
Design/Subjects: Laboratory investigation utilizing a HNSCC cell line, HSC-3.
Interventions: Rho kinase and PI-3 kinase activity, myosin phosphatase and AKT phosphorylation, tumor cell growth, migration, and MMP secretion were measured in the presence or absence of HA, cisplatin, and inhibitors of Rho kinase and PI-3 kinase.
Results: The addition of HA, but not HA plus anti-CD44 antibody, resulted in increased Rho kinase and PI-3 kinase activity. Immunoblotting studies demonstrated that HA promotes Rho kinase mediated myosin phosphatase phosphorylation and PI-3 kinase mediated AKT phosphorylation. HA was shown to promote migration and increased MMP secretion through Rho kinase mediated signaling. HA treatment promoted increased tumor proliferation and resulted in a 12-fold reduced ability of cisplatin to cause HNSCC cell death. On the other hand, the presence of Y-27632, a Rho kinase inhibitor, and LY-294002, a PI-3 kinase inhibitor, blocked HA-mediated cisplatin resistance.
Conclusions: Our results suggest that HA and CD44 promote Rho kinase and PI-3 kinase mediated oncogenic signaling and cisplatin resistance. Perturbation of HA-CD44 mediated Rho kinase and PI-3 kinase signaling pathways may be a novel strategy to treat HNSCC.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4121.
Abstract 4131: Activation of PKC-delta inhibits apoptosis leading to mitomycin C resistance
Authors: Khatri Raju , Niture Suryakant K. , Jaiswal Anil K. 
Published: February 2011

Abstract
Antioxidant-induced protein kinase C delta (PKCdelta) is known to phosphorylate cell survival transcription factor Nrf2. Phosphorylated Nrf2 translocates to the nucleus leading to coordinated activation of detoxifying enzyme gene expression. This mechanism is critical for protection against chemical and radiation stress and cell survival. Human breast cancer MCF-7 cells expressing endogenous PKCdelta, human breast cancer BT549 cells deficient in PKCdelta expression (PKCdelta-null) and BT549-C1 cells expressing cDNA derived PKCdelta demonstrated differential survival and apoptotic death responses to anti-tumor drug mitomycin C. MCF-7 and BT549-C1 cells expressing PKCdelta showed increased survival and decreased apoptotic cell death as compared with PKCdelta-null BT549 cells. The studies also demonstrated that mitomycin C induced serine40 phosphorylation and nuclear translocation of Nrf2. Further studies determined that Nrf2 translocation in the nucleus led to an increase in Bcl2 and BclXL expression that contributed to the inhibition of apoptosis, increased cell survival and mitomycin C resistance. Interestingly, inclusion of antioxidant tert-butyl hydroquinone with mitomycin C further enhanced the PKCdelta effect on cell survival and apoptotic cell death. These results led to the conclusion that PKCdelta is endogenous factor in drug resistance and could serve as a therapeutic target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4131.
Abstract 4137: Verification of antitumor effect of γ-secretase-inhibitor and radiotherapy
Authors: Mizugaki Hidenori , Konishi Jun , Kikuchi Junko , Kikuchi Eiki , Shinagawa Naofumi , Oizumi Satoshi , Nishimura Masaharu 
Published: February 2011

Abstract
[Background and Aim] Notch3 is a member of the Notch signaling pathway, which plays an important role in cancer development. We have already demonstrated that Notch3 is over-expressed in approximately 40% of lung cancer tumors and that inhibition of the Notch3 pathway by γ-secretase-inhibitor (GSI) induces apoptosis and suppresses tumor growth in lung cancer. Although a previous report has shown that radiation enhanced Notch1 expression in breast cancer, little is known about the relationship between radiation and Notch pathway. In this study, we attempt to elucidate the combined effect of GSI and radiotherapy in lung cancer. [Results] We used two Notch3-expressing lung cancer cell lines (HCC2429 and H460). In a MTT proliferation assay and clonogenic assay, combination of GSI and radiation suppressed the growth of lung cancer cells and colony formations compared to GSI or radiation alone. We also showed that GSI down-regulates Notch3 expression in a dose dependent manner, and radiation up-regulates Notch expression and downstream Notch target gene, Hey-1. Notch up-regulation by radiation is down-regulated by the combination. Combination of GSI and radiation reduced p-Bcl2, Bcl-XL and p-Erk compared to GSI or radiation alone, whereas no effect on p-Akt level was seen.[Conclusion] Our results suggest that combination of GSI and radiation may be clinical potential strategy in the treatment of patients with lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4137.
Abstract 4142: The effects of SBHA on Notch 1 expression and platinum sensitivity in ovarian cancer cells
Authors: Rose Stephen L. , Kunnimalaiyaan Muthusamy , Drenzek Jessica , Seiler Nicole 
Published: February 2011

Abstract
Objective: Despite advances in radical surgical debulking and intraperitoneal chemotherapy, ovarian cancer remains the most deadly gynecologic malignancy. The Notch signaling pathway plays an important role in cellular differentiation, proliferation, and apoptosis. We have previously found Notch 1 intracellular domain (NICD) to be highly expressed in the most platinum resistant ovarian cancer cell lines. Recent evidence has shown that histone deacetylase inhibitors (HDACi's) decrease platinum resistance in oral squamous cell cancers. In addition, the HDACi suberoyl bis-hydroxamic acid (SBHA) has been found to modify Notch 1 expression in other cancers. We hypothesized that SBHA would reduce ovarian cancer cell proliferation through inhibition of the Notch 1 signaling pathway and help sensitize ovarian cancer cells to platinum.
Methods: Following treatment with SBHA, NICD expression in the ovarian carcinoma cell lines OVCAR3, SKOV3, and CaOV3 was analyzed by Western blot. The effects of SBHA and cisplatin on ovarian cancer cell growth were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) growth assay.
Results: NICD expression by Western blot was consistently reduced in all 3 cell lines following treatment with SBHA. Dose-dependent growth inhibition of ovarian cancer cells was demonstrated with SBHA treatment. Furthermore, the addition of SBHA to cisplatin resulted in additional reduction of NICD and further growth suppression in SKOV3, the most platinum resistant cell line tested.
Conclusions: SBHA treatment of ovarian cancer cells led to decreased NICD expression and dose dependent growth reduction in ovarian cancer cells. In addition, we found that SBHA in combination with platinum further reduced NICD expression and growth in SKOV3 cells. These findings provide a compelling argument for further study into the role that Notch 1 signaling may be playing in platinum resistance and ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4142.
Abstract 4143: Bz-423, a novel benzodiazpine, inhibits PI3 kinase signaling in ovarian cancer cells
Authors: Garg Gunjal , Liu Rebecca , Boitano Anthony , Tan Lijun , Kwok Roland , Glick Gary , Opipari Anthony 
Published: February 2011

Abstract
Objective: Bz-423 is a 1,4-benzodiazepine with immunomodulatory and cytotoxic properties. The effect of Bz-423 on survival signaling in lymphoid neoplasms predicts activity against similar pathways in ovarian cancer cells. Having previously established the cytotoxic activity of Bz-423 against ovarian cancer, we now characterize the mechanism of action.
Methods: Human ovarian cancer cell lines were maintained in culture. Cells were treated with Bz-423 or vehicle control. Cell survival and proliferation were evaluated, along with signaling mechanisms including the PI3-kinase-Akt-mTOR axis. DNA degradation (apoptotic fraction), mitochondrial function and caspase activation were evaluated by flow cytometry. Cytochrome c release and protein kinase activation were analyzed by immunoblotting. Apoptosome complex formation was monitored by gel filtration chromatography. Cellular ultrastructure was determined by electron microscopy (EM).
Results: Growth inhibition and apoptosis were observed in all ovarian cell lines following treatment with Bz-423. Caspase-9 and −3 cleavage, along with cytochrome c release were seen, consistent with activation of the intrinsic pathway of apoptosis. Early mitochondrial changes identified by ultrastructural evidence of mitochondrial swelling and the accumulation of superoxide within 1 hr of treatment were seen. Bz-423 induced cell death was associated with inhibition of Akt activation through a oxidant dependent mechanism. Antioxidants blocked Bz-423-induced signaling.
Conclusions: Bz-423 is a novel benzodiazepine being developed as a mitochondria targeted therapy, and displays anti-neoplastic activity against ovarian cancer cells in vitro. Results show that by acting on mitochondrial complex V, this compound inhibits PI3-kinase signaling, including the tumor survival factor Akt. PI3-kinase signaling is increasingly recognized as a survival and growth promoting mechanism in ovarian cancer. Since Akt inhibition by Bz-423 is dependent upon cellular bioenergetics and anti-oxidant balance, strategies employing this compound offer a selective new approach to target ovarian cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4143.
Abstract 4145: Increased anti-tumor effect of sorafenib by depleting tumor associated macrophages
Authors: Hui-Chuan Sun , Zhang Wei , Zhu Xiao-Dong , Tang Zhao-You 
Published: February 2011

Abstract
Background: Sorafenib prolonged survival in patients with unresectable hepatocellular carcinoma (HCC), but the effect is modest and tumor finally progressed even under continuous sorafenib therapy. The aim of this study is to investigate the mechanism of tumor progression under sorafenib treatment.
Methods: Tumor growth, local invasion and lung metastasis were observed in MHCCLM3-R, a human HCC xenograft nude mouse model, when treated by sorafenib (30 mg/kg qd, n=6 per group) and vehicle as control. Macrophage infiltration was measured in the peripheral blood and macrophage in tumor after sorafenib treatment by immunohistochemistry and flow cytometry with F4/80 antibody, and the effect of macrophage depletion on tumor angiogenesis and metastasis after sorafenib treatment, using two drugs target macrophages, zoledronic acid (ZA) and clodrolip, in a mouse model of human hepatocellular carcinoma (HCC).
Results: Sorafenib treatment significantly inhibited tumor growth and lung metastasis, but also induced significant increase in peripheral F4/80-positive cells and intratumoral macrophages infiltration, which was associated with elevation of colony stimulating factor-1, stromal-derived factor 1α and vascular endothelial growth factor in tumor and plasma VEGF of mouse origin in peripheral blood, suggesting the role of macrophage in tumor progression during sorafenib treatment. Depletion of macrophage by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis and lung metastasis compared to that of mice treated with sorafenib alone. ZA was more effective than clodrolip.
Conclusions: Macrophage may have an important role in tumor progression under sorafenib treatment. Zoledronic acid is promising when combined with sorafenib to enhance its anti-tumor effect.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4145.
Abstract 4146: Quantitative cell signaling analysis for cetuximab sensitivity prediction in colorectal cancer
Authors: Teppei Matsuo , Nishizuka Satoshi , Iwaya Takeshi , Ishida Kazushige , Noda Hironobu , Ikeda Miyuki , Kozai Megumi , Wakabayashi Go 
Published: February 2011

Abstract
[Background]
Anti-human EGFR monoclonal antibody (cetuximab) has been widely used in the treatment of colorectal cancer (CRC). However it is thought that a reliable predictor for therapeutic efficacy should be established because the benefit of cetuximab treatment is often still uncertain. Our preliminary study showed that the prediction of therapeutic efficacy using a conventional chemosensitivity test using growth suppression assay is generally not informative because cetuximab does not seem to have as strong a cytotoxicity as other anticancer drugs. KRAS mutation status has been used as a biomarker to predict therapeutic efficiency but it is not sensitive enough to determine the absolute indication.
[Purpose]
We hypothesized that we could predict therapeutic efficacy by evaluating expected molecular reaction when cetuximab is administrated in vitro. In the present study, we build up an in vitro EGFR signaling model for a new chemosensitivity test based on protein monitoring in response to cetuximab administration.
[Materials and Methods]
Three growth factors (EGF, TGF-α, and IGF) and the inhibitor (cetuximab) were added to HT29 (KRAS wild type, EGFR positive) in six combinations. Cell pellets were harvested at 5 time points over a 15min time course, each of which was processed for cell lysate. The lysates were analyzed by Western blotting to see if the proteins involved in the EGFR signaling pathway responded over time.
[Results]
We confirmed the activation of signaling stimulated by EGF, TGF-α, and IGF; and the effect on signaling by cetuximab in HT29 with Western blotting. Intriguingly, the phosphorylation level of EGFR was rapidly elevated and declined by EGF stimulating in the absence of cetuximab whereas dephosphorylation was prolonged in the presence of cetuximab. In the administration of either TGF-α or IGF, the phosphorylation pattern of EGFR, c-RAF, MEK, MAPK, ERK, PI3K, AKT, PTEN, and STAT was different from that of EGF alone.
[Conclusions]
These results shows that:(i) EGF is not EGFR's only ligand; (ii) cetuximab can't inhibit every signaling pathway starting from EGFR; and (iii) TGF-α and IGF activate signaling pathway starting from EGFR partially but not thoroughly. An additional reliable predictor of cetuximab efficacy should be identified based on functional protein characteristics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4146.
Abstract 4147: Xanthohumol decreases Notch1 expression and cell growth in human epithelial ovarian cancer cell lines
Authors: Drenzek Jessica , Seiler Nicole , Rose Stephen 
Published: February 2011

Abstract
Epithelial ovarian cancer is the most lethal of all gynecologic malignancies in the United States with the majority of cases detected with advanced disease. Therefore, it is critical that novel therapies be developed that can effectively treat ovarian cancer. Notch1 is a transmembrane receptor that upon activation is cleaved by gamma-secretase resulting in Notch1 intracellular domain (NICD) translocation to the nucleus where it heterodimerizes with the transcription factor CBF-1 converting CBF-1 from a transcriptional repressor to a transcriptional activator via recruitment of coactivators. Deregulation of the Notch pathway has been observed in cancers such as T cell lymphoblastic leukemia, pancreatic, and breast. In addition, it has been shown that NICD is expressed in ovarian cancer cell lines and ovarian tumors. Xanthohumol, a prenylated chalcone derived from hops used in brewing beer, has been shown to exhibit anti-cancer properties. Since xanthohumol has been shown to inhibit cancer cell growth and invasion, we hypothesized that the Notch1 signaling pathway is suppressed by xanthohumol leading to decreased cell growth. OVCAR3 and SKOV3 are human epithelial ovarian cancer cell lines that express high levels of NICD. These cells were treated with increasing doses of xanthohumol, and cell growth was measured by 3-[4,5-dimethylthiazole-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay on days 0, 2, 4, and 6. In addition, protein lysates were isolated on days 2 and 4 of treatment, detected by western blot using a NICD primary antibody, and protein expression was evaluated by densitometry. These treatments resulted in decreased cell growth when measured by MTT assay. In addition, when analyzed by western blot, there was a decrease in NICD protein expression. In conclusion, xanthohumol was a potent inhibitor of ovarian cancer cell growth, and our results suggest that xanthohumol is affecting the Notch pathway. Therefore, it is essential that further investigation into the role that xanthohumol has on the Notch pathway be pursued. These outcomes could prompt the use of xanthohumol as a potential chemotherapeutic agent in ovarian cancer patients who do not respond long term to standard chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4147.