bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1046: Differential interactions between c-Src and c-Met mediate resistance to c-Src inhibitors
Authors: Sen Banibrata , Peng Shaohua , Saigal Babita , Williams Michelle , Johnson Faye M. 
Published: June 2012

Abstract
Cancers of the head and neck are difficult to treat because both the therapy and the tumor impact essential functions such as speech and swallowing and they can also significantly alter facial appearance. One promising molecular target for which new agents have been developed is the Src family kinases (SFKs). SFK inhibition in cancer cells leads to an universal abrogation of invasion but a variable and weak effects on apoptosis and proliferation. The pathways downstream of c-Src promoting survival are not well-characterized. Because cancer therapy that both decreases invasion and induces significant apoptosis would be ideal for head and neck cancers, we sought to characterize the mechanisms of resistance to SFK inhibition in Head and Neck squamous cell carcinoma (HNSCC). SFKs were inhibited in a panel of oral cancer cell lines and the effects on subsequent survival and signaling were measured. The interactions between c-Src and c-Met were evaluated using immunoprecitation and their intrinsic kinase activity by in vitro kinase assay. Cytotoxicity was measured using an MTT assay and the Chou-Talalay combination index calculated. The in vivo effects of c-Met and SFK inhibitors were assessed using an orthotopic model of oral cancer. SFK inhibition resulted in c-Met inhibition in cell lines that were sensitive to SFK inhibitors, but not in resistant cell lines. Isolated c-Met act as a c-Src substrate in both sensitive and resistant cells, whereas distinct difference exists in c-Src and c-Met interaction in intact sensitive and resistant cells. The epidermal growth factor receptor contributed to c-Met activation in resistant cells whereas in sensitive cells c-Met acts as a direct downstream target for c-Src. We demonstrated the biological consequences of this mechanism in vitro with synergistic cytotoxicity and enhanced apoptosis when SFK and c-Met inhibitors were combined. Likewise, the combination resulted in decreased tumor size in vivo. In conclusion, we demonstrate that sustained c-Met activation can mediate resistance to SFK inhibition. The differences between c-Src and c-Met signaling in sensitive and resistant cells are not due to intrinsic structural changes in c-Src or c-Met, but rather to distinct interactions within the intact cells. The synergistic cytotoxic effects of SFK and c-Met inhibition may be important for the treatment of head and neck cancers and should be tested in future clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1046. doi:10.1158/1538-7445.AM2011-1046
Abstract 105: An epigenetic vicious cycle of DNMT, protein Tyrosine phosphatase receptor type R, and the MAPK pathway in cancer metastasis
Authors: Su Po-Hsuan , Lin Ya-Wen , Liao Yu-Ping , Wang Yu-Chi , Lee Hsin-Yi , Wang Hui-Chen , Chao Tai-Kuang , Chen Chi-Kuan , Chan Michael W.Y. , Chu Tang-Yuan , Yu Mu-Hsien , Lai Hung-Cheng 
Published: June 2012

Abstract
Introduction: Epigenetic modifications are a driving force in carcinogenesis. In addition to its role in initiation and promotion, DNA methylation is thought to participate in cancer metastasis. The present study is to interrogate the role of de novo DNA methylation in cervical cancer invasions.
Methods and Results: Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and that DNMT3B interference inhibits metastasis. Using methyl-DNA immunoprecipitation coupled with microarray analysis (mDIP-on-chip), we found that Protein Tyrosine Phosphatase Receptor Type R (PTPRR) is targeted by DNMT3B. PTPRR inhibited metastasis by inhibiting p44/42 MAPK signaling, epithelial-mesenchymal transition (EMT), and matrix metalloproteinase 9 (MMP9) expression. PTPRR also inhibited the expression of transcription factor AP1, HPV oncogenes, and DNMTs, and reciprocally demethylated the PTPRR promoter. The methylation status of PTPRR was increased in cervical scrapings in accordance with disease severities, and immunohistochemical staining confirmed that PTPRR protein was expressed in precancerous lesions but was silenced in invasive cancers. The clinical correlation results suggest that methylation of the PTPRR promoter is a potential biomarker for cervical cancer detection.
Conclusion: This study demonstrates for the first time that DNMT3B plays an important role in the cervical cancer invasion and metastasis. The DNMT3B-mediated silencing of PTPRR activates p44/42 MAPK signaling and its multiple downstream effectors such as EMT, enabling the in situ tumors becoming invasive. MAPK signaling also augments the expression of DNMTs, which further consolidates the methylation silencing of PTPRR. A vicious cycle between epigenetic machinery and oncogenic signaling promotes cancer metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 105. doi:10.1158/1538-7445.AM2011-105
Abstract 1058: LKB1 negatively regulates IGF-1 induced ERK phosphorylation
Authors: Zhong Diansheng , Liu Xiuju , Fu Haian , Sun Shi-Yong , Khuri Fadlo R. , Zhou Wei 
Published: June 2012

Abstract
The LKB1/AMPK metabolic checkpoint can be activated by various energetic stresses, and a common reagent to induced LKB1/AMPK signaling is 2-deoxyglucose (2-DG), a glycolytic inhibitor. We recently discovered a novel function of 2-DG because it is capable of disrupting the interaction between IGF-1 and IGFBP3 to release free IGF-1 and activate IGF1R signaling. Therefore, 2-DG activates LKB1/AMPK and IGF1R signaling pathways through two distinct mechanisms. Interestingly, while 2-DG induced IGF1R signaling activates PI3K/Akt function in most cell lines; the induction of MEK/ERK signaling was only observed in some cancer cells. Here, we demonstrated that 2-DG induced ERK phosphorylation in LKB1 mutant cells but suppressed ERK phosphorylation in cells with wild-type LKB1. The phenomenon is LKB1-dependent because restoration of LKB1 expression in LKB1-null cells attenuated IGF-1 induced ERK phosphorylation, and the depletion of LKB1 by RNAi in LKB1-wild type cells promoted ERK phosphorylation. Mechanistically, LKB1 mediates ERK suppression through its down-stream target, AMPK, as the inhibition of AMPK function either by RNAi or small molecular inhibitors promotes IGF-1 induced ERK phosphorylation. In summary, this study has demonstrated a novel function of LKB1/AMPK in the negative regulation of IGF-1 induced ERK signaling. (This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award, NIH/NCI PO1 CA116676-030002. SY Sun, FR Khuri and W Zhou are Georgia Cancer Coalition Distinguished Cancer Scholars. W Zhou is an American Cancer Society Research Scholar.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1058. doi:10.1158/1538-7445.AM2011-1058
Abstract 1072: Activation of the Ras signaling pathway promotes the over-expression of anti-apoptotic heme oxygenase-1 in human renal cancer
Authors: Banerjee Pallavi , Basu Aninda , Pal Soumitro 
Published: June 2012

Abstract
Activation of the proto-oncogene ras may play a critical role in the development and rapid progression of different types of human cancers, including renal cancer. It has been shown that the Ras pathway can mediate pro-survival signals in cancer cells by inhibiting cellular apoptosis. It is established that the cytoprotective enzyme heme oxygenase-1 (HO-1) is over-expressed in several cancers, and may play a significant role in the growth and metastasis of tumors by inducing cell survival pathways. However, it is not known if there is an association between Ras activation and HO-1 over-expression in cancer. We have recently demonstrated that the treatment of human renal cancer cells with the immunosuppressive agent cyclosporine may activate the H-Ras pathway, and promote a rapid progression of the disease. We have also shown that HO-1 is over-expressed in human renal cancer, and plays a key role in the survival of renal cancer cells by inhibiting cellular apoptosis. Here, we wished to analyze if the activation of H-Ras pathway can regulate the expression of HO-1 in two different human renal cancer cell lines 786-0 and Caki-1. In co-transfection assays, using a full-length HO-1 promoter-luciferase construct, we found that the activated form of H-Ras (H-Ras12V) promoted HO-1 transcriptional activation as observed by increased luciferase activity. We also found that the activation of H-Ras increased the mRNA expression of HO-1 as observed by real-time PCR. By using a dominant-inhibitory mutant construct H-Ras17N, we confirmed that the inhibition of H-Ras expression significantly decreased HO-1 promoter activity. We next wanted to determine which effector molecule(s) (Raf, Rho and PI-3K) is functional for H-Ras-mediated HO-1 over-expression. We made use of three different effector domain mutant constructs of H-Ras; Ras(12V,35S) retains full-length Raf-1 binding activity, Ras(12V,37G) retains Rho binding activity, and Ras(12V,40C) retains PI-3K binding activity. In co-transfection assays using these effector domain mutant constructs, we observed that the Ras-induced HO-1 transcriptional activation is mediated primarily through the Raf-1 signaling pathway. Together, our findings suggest that the Ras-Raf signaling pathway might play an important role in the survival of human renal cancer cells through the induction of HO-1 over-expression. Thus, targeting this H-Ras pathway for HO-1 over-expression might act as novel therapeutics to inhibit human renal tumors through the induction of cellular apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1072. doi:10.1158/1538-7445.AM2011-1072
Abstract 1073: A systematic approach to identify the Ras-dependent C-RAF(Ser338)-phosphorylating kinase
Authors: Johannessen Cory M. , Boehm Jesse , Hamm Luke , Yang Xiaoping , Garraway Levi 
Published: June 2012

Abstract
Phosphorylation of c-RAF at Ser338 is an absolute requirement for c-RAF activation and Ras-mediated signaling; however, definitive identification of the c-RAF(Ser338)-phosphorylating kinase has remained elusive. As a first step towards this end, we screened a collection of ∼600 expressible kinase open reading frames to determine which are sufficient to induce phosphorylation of c-RAF on Ser338. In total, 12 kinases induced c-RAF(Ser338) phosphorylation, including 9 Ser/Thr kinases, 1 kinase with unknown site specificity, 1 adapter factor and 1 scaffolding protein. Notably, two proteins previously shown to regulate c-RAF(Ser338) phosphorylation (PAK3 and KSR) also scored in this assay, highlighting the utility of this approach to uncover plausible effectors. We have initiated follow-up studies, including recombinant protein-based kinase assays and loss of function experiments, to characterize the kinase(s) responsible for Ras-mediated c-RAF(Ser338) phosphorylation in vivo. Given the inherent difficulty of targeting Ras-dependent cancers, a more detailed understanding of c-RAF phosphorylation and Ras-dependent activation may inform new therapeutic inroads to targeting these lesions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1073. doi:10.1158/1538-7445.AM2011-1073
Abstract 1074: Dishevelled 3 (Dvl3) is upregulated and enhances cell migration and invasion in hepatocellular carcinoma
Authors: Tsui Yu Man , Tung Edmund Kwok-Kwan , Mak Carmen Ka-Man , Ng Irene Oi-Lin 
Published: June 2012

Abstract
Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies in the world and is particularly prevalent in China and Southeast Asia. Although the risk factors are well known, the molecular mechanisms underlying hepatocarcinogenesis is unclear. Alteration of Wnt signaling pathway is one of the key events in HCC development and so we performed a low-density array (LDA) analysis on 38 pairs of HCC samples and their corresponding non-tumorous livers to examine the expression profiles of different Wnt signaling components. We found that, among the genes studied, Dishevelled 3 (Dvl3) was significantly overexpressed in HCCs as compared with the corresponding non-tumorous liver tissues. In addition, Dvl3 overexpression in HCC was significantly associated with presence of venous invasion (P = .021). The overexpression result was confirmed by expansion of the sample size using quantitative real-time PCR (q-PCR). Next, we investigated the effects of Dvl3 on the migratory and invasive abilities of HCC cells. We established stable shRNA Dvl3-knockdown clones in PLC/PRF/5 HCC cells and found that knockdown of Dvl3 suppressed the migratory and invasive abilities of HCC cells using transwell migration and invasion assays, respectively, suggesting an enhancing role of Dvl3 in HCC cell movement and cell invasion. Although cell proliferation assay in vitro showed no significant difference between the stable Dvl3 knockdown and non-target control PLC/PRF/5 cells, in vivo study in SCID mice showed that the stable Dvl3-knockdown cells resulted in a lower incidence of tumors formed and a smaller tumor size. Furthermore, since Dvl3 is an upstream regulator of the Wnt/β-catenin pathway, using the TOPFOP luciferase reporter assay, we found that transient transfection of Dvl3 in PLC/PRF/5 and BEL-7402 HCC cell lines enhanced the β-catenin-dependent transcriptional activity. In conclusion, upregulation of Dvl3 was frequent in human HCCs. Dvl3 enhanced cell migration and invasion in vitro and tumorigenicity in vivo in SCID mice, and activated canonical β-catenin pathway. It may play an oncogenic role in HCC development.
(This study was funded by Hong Kong Research Grants Council CRF grants (RGC CRF HKU1/06C and HKU 7/CRG/09).)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1074. doi:10.1158/1538-7445.AM2011-1074
Abstract 1078: PPM1A acts as a novel RelA phosphatase to negatively regulate NF-κB signaling
Authors: Lu Xinyuan , An Hanbing , Yarbrough Wendell G. 
Published: June 2012

Abstract
Phosphorylation of RelA is required to fully activate NF-κB transcription activity and dephosphorylation of RelA can inhibit its activity. To date, Wip1 (PPM1D) and PP2A have been described as RelA phosphatases. The purpose of this study was to identify novel RelA phosphatase(s) and determine if they play a role in regulation of NF-κB activity related to tumorigenesis. PPM1A belongs to PP2C protein phosphatase family, the same family of Wip1. To begin exploring PPM1A activity toward RelA, serine 536 (S536) phosphorylation of RelA was determined with and without expression or knockdown of PPM1A. Expression of PPM1A in U2OS cells decreased RelA phosphorylation, whereas siRNA-mediated loss of PPM1A increased S536RelA phosphorylation. Luciferase assay using a κB responsive reporter with expression of either PPM1A or phosphatase-dead PPM1A (PPM1A-PD) revealed that wild-type, but not PPM1A-PD, inhibited RelA transcription. Furthermore, in vitro phosphatase assays using bacterially expressed PPM1A with substrate of either full length RelA or phosphorylated RelA peptides, suggest that PPM1A can function as a direct RelA phosphatase at residuesS536 and S276. We could not identify reports of additional phosphatases with activity toward the S276 residue of RelA. Using liquid chromatography and tandem mass spectroscopy (LC-MS/MS) LZAP-associated proteins (LAPs) were sought with PPM1A being identified. LZAP (C53, CDK5RAP3) has tumor suppressor-like activity that is mediated at least partially through inhibition of RelA S536 phosphorylation and activity. PPM1A's ability to decrease RelA phosphorylation at S536 site was largely inhibited in cells with siRNA-mediated loss of LZAP. To determine if PPM1A has tumor suppressor activity, HeLa cells were infected with retrovirus directing shRNA-mediated knockdown of PPM1A and tumorigenic properties of these cells were determined. Preliminary xenograft tumor data suggest PPM1A has a negative effect on tumor initiation and proliferation and studies are underway to determine if PPM1A activity toward NF-κB plays a role. In summary, our data suggest that PPM1A is a novel RelA phosphatase with activity to dephosphorylate RelA at serines 536 and 276. PPM1A inhibits NF-κB transcriptional activity and that PPM1A activity toward RelA is at least partially dependent on LZAP. Our preliminary data also suggest PPM1A might have tumor suppressor-like activity that could be dependent on LZAP or RelA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1078. doi:10.1158/1538-7445.AM2011-1078
Abstract 1079: Function and modulation of Pdcd4 in ovarian cancer
Authors: Liu Stephanie S. , Wei Tina N. , Chan Karen KL , Ngan Hextan YS 
Published: June 2012

Abstract
Programmed cell death 4 (Pdcd4), a novel gene and originally identified as the neoplastic transformation inhibitor, is attenuated in various cancer types. It has been shown to have tumor suppressor properties such as inhibiting cell proliferation and inducing apoptosis. Our previous study demonstrated a continuous down-regulation of Pdcd4 expression in the sequence of normal-borderline-malignant ovarian tissue samples, and a significant correlation of Pdcd4 expression with disease-free survival. The objective of the current study is to further investigate the function and modulation of Pdcd4 in ovarian cancer cells.
Our in vitro studies demonstrated that ectopic Pdcd4 expression significantly inhibited ovarian cancer cell proliferation by up-regulation of cyclin dependent kinase inhibitors of p27 and p21 and subsequently leading to cell cycle arrest at G1 stage. Unlike other cancers, Pdcd4 neither induce ovarian cancer cell apoptosis, nor promote the cellular sensitivity in response to cisplatin treatment. Pdcd4 over-expressing ovarian cancer cells exhibited elevated phosphatase and tensin homolog (PTEN) and decreased p-Akt expressions. In addition, Pdcd4 expression was up-regulated and translocated from cell nucleus to cytoplasm upon serum withdrawal treatment, but was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of Pdcd4.
In conclusion, loss of Pdcd4 may result in diminished cell ability to arrest at key checkpoint, leading to tumor development. The PI3K-Akt pathway may be involved in the regulation of Pdcd4 degradation in ovarian cancer cells. In response to the stress condition, Pdcd4 expression was altered and it was translocated to cytoplasm, suggesting that Pdcd4 was able to shuttle between cell compartments to perform its diverted functions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1079. doi:10.1158/1538-7445.AM2011-1079
Abstract 1083: Caveolin-1 in cutaneous squamous cell carcinoma development
Authors: Trimmer Casey , Katiyar Sanjay , Pestell Richard G. , Lisanti Michael P. , Capozza Franco 
Published: June 2012

Abstract
Caveolin-1 (Cav1) is the main protein component of a specialized form of lipid raft termed caveolae and serves to compartmentalize and negatively regulate the activity of signaling molecules involved in cell proliferation and survival. Cav1 has been shown to act as a tumor suppressor in several types of cancer, including breast cancer and melanoma, but its role in the pathogenesis of non-melanoma skin cancer remains largely unexplored. Previous work has indicated that Cav1 is expressed in the basal cell layer of both murine and human epidermis; additionally, loss of Cav1 protein has been shown by our lab to render murine skin more susceptible to papilloma development following treatment with a carcinogenic compound. The purpose of the current study was to further examine the role of Cav1 in non-melanoma skin cancer development using various experimental approaches.
Given the previous research, our hypothesis is that Cav1 acts as a suppressor of tumor growth and development in the skin. In order to explore this hypothesis, we have used several experimental systems, including human tissue arrays and loss of function and gain of function studies in animal models of cutaneous squamous cell carcinoma. Manipulation of Cav1 expression in (1) a keratinocyte cell line followed by xenotransplantation and (2) an induced model of skin cancer allowed us to assess the effect of this protein on tumor development, growth, and progression. Using these approaches, we were able to show that Cav1 ablation dramatically increases not only in vitro cell growth and invasion, but also in vivo tumorigenesis, tumor growth, and invasion. In conclusion, these studies provide further evidence in support of the hypothesis that Cav1 acts as a tumor suppressor protein in the skin and serve to identify new potential therapeutic targets in the treatment of cutaneous malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1083. doi:10.1158/1538-7445.AM2011-1083