tbuckley/cabot-search huggingface dataset:
Abstract 1360: Novel function of p21-activated kinase 3 (PAK3) in regulating Akt phosphorylation and pancreatic cancer stem cell phenotypes
Authors: Hsing-Yu Wu, Ming-Chen Yang, Po-Chen Chu, Samuel K. Kulp, Ching-Shih Chen
Journal: Cancer Research (2017)

Abstract p21-activated kinases (PAKs) are important effectors of the Rho family GTPases and has been implicated in cytoskelestal remodeling, cell proliferation, apoptosis, and transformation. Based on the sequence, structure homology, and activation mechanism, six PAKs are classified into two groups, PAK 1-3 (group I) and PAK 4-6 (group II). PAK kinases are frequently overexpressed in various human tumors and represent therapeutically relevant targets for cancer treatments. Previous studies have shown that PAK1 and PAK4 are upregulated and/or hyperactivated in pancreatic cancer, and promotes pancreatic cancer cell motility and invasion. In our study, we showed that knockdown of PAK3, but not that of PAK1 or PAK2, inhibited pancreatic cancer cell proliferation in vitro, and tumor growth in vivo. In addition, our data showed that PAK3 regulated the protein stability of β-catenin via Akt/GSK-3β signaling pathway in pancreatic cancer cells. The role of PAK3 in regulating Akt/GSK-3β phosphorylation was further confirmed by the ectopic expression of wild-type versus kinase-dead (K297L) PAK3. Equally important, the mammosphere formation, aldehyde dehydrogenase (ALDH) activity and cancer stem cell-associated markers, were also down-regulated in PAK3 knockdown cells, suggesting the involvement of PAK3 in regulating cancer stem cell-like properties in pancreatic cancer cells. Together, these findings suggested that PAK3 as a primary regulator of Akt/GSK-3β/β-catenin signaling for maintaining cancer stem cell phenotypes and promoting tumor growth, which underlies the potential of targeting PAK3 in fostering new therapeutic strategies for pancreatic cancer. Citation Format: Hsing-Yu Wu, Ming-Chen Yang, Po-Chen Chu, Samuel K. Kulp, Ching-Shih Chen. Novel function of p21-activated kinase 3 (PAK3) in regulating Akt phosphorylation and pancreatic cancer stem cell phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1360. doi:10.1158/1538-7445.AM2017-1360
Abstract 199: Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways
Authors: Mitsuho Imai-Sumida, Takeshi Chiyomaru, Shahana Majid, Priyanka Kulkarni, Pritha Dasgupta, Sharanjot Saini, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Guoren Deng, Varahram Shahryari, Hannah Nip, Rajvir Dahiya, Yuichiro Tanaka, Soichiro Yamamura
Journal: Cancer Research (2017)

Abstract Silibinin is the major active constituent of silymarin, an extract of milk thistle seeds. Silibinin has been shown to have significant anti-cancer effects in a variety of malignancies. However, the molecular mechanisms of silibinin action in bladder cancer have not been studied extensively. In the present study, we found that silibinin (10 μM) significantly suppressed proliferation and invasion of T24 and UM-UC-3 human bladder cancer cells. In this study, we investigated the molecular mechanisms underlying these effects of silibinin. Our results showed that silibinin down-regulates actin cytoskeleton-related Ras-Rac-PAK1 pathways and the phosphatidylinositide 3-kinase (PI3K)/Akt signaling pathway in these bladder cancer cell lines. These pathways were found to promote cellular transformation and cancer development and have crosstalk through Ras cascades. We investigated the role of silibinin on Ras, and found that silibinin suppresses levels of trimethylated histone H3 lysine 4 and acethylated H3 at the K-RAS promoter. We also found that silibinin downregulates long non-coding RNAs: HOTAIR and ZFAS1, which are known to play roles as oncogenic lncRNAs in various cancers. This study shows that silibinin exerts anti-cancer effects through down-regulation of the actin cytoskeleton and PI3K/Akt pathways and thus suppresses the development and progression of bladder cancer. Citation Format: Mitsuho Imai-Sumida, Takeshi Chiyomaru, Shahana Majid, Priyanka Kulkarni, Pritha Dasgupta, Sharanjot Saini, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Guoren Deng, Varahram Shahryari, Hannah Nip, Rajvir Dahiya, Yuichiro Tanaka, Soichiro Yamamura. Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 199. doi:10.1158/1538-7445.AM2017-199
Abstract 4448: Elevated levels of circulating miR-34a-5p and miR-181c-3p during cancer initiation by aflatoxin B1
Authors: Merricka C. Livingstone, Bill D. Roebuck, Natalie M. Johnson, Thomas W. Kensler, John D. Groopman
Journal: Cancer Research (2017)

Abstract MicroRNAs are small non-coding RNAs that affect gene expression. They are essential in normal physiological processes and have been implicated in carcinogenesis. Hepatocellular carcinoma (HCC) is the second leading cause of cancer death globally, with the risk factor aflatoxin (AFB1) estimated to play a causal role in up to 28% of all HCC cases. In this study, we analyzed circulating miRNAs in a quantitative rat cancer model that were previously found to be associated with AFB1 exposure in liver. Sera were examined from 3 groups of animals: rats dosed with AFB1 (200 µg) for 28 consecutive days receiving vehicle only or AFB1 plus the chemopreventive agent CDDO-Im (30 µmol), and controls (Johnson et al., CaPR, 2014). Small RNAs were isolated from these serum samples at the end of the dosing period and analyzed by RT-qPCR. Quantitative PCR results at the end of the carcinogenic 28-day dosing regimen revealed notable increased expression of miR-34a-5p and miR-181c-3p (13 fold and 170 fold, respectively) in the AFB1 treated samples compared to controls. This expression was reduced in animals that received complete protection from developing HCC by concurrent intervention with CDDO-Im. Additionally, miR-122-5p displayed increased expression (5 fold) and miR-541-5p was downregulated (0.08 fold) in the sera of AFB1-treated animals. Overall, the data suggest that serum expression of miR-34a-5p and 181c-3p during liver cancer initiation could give insight into increased risk of developing HCC. Supported by T32ES007141-31A1 and CA197222. Citation Format: Merricka C. Livingstone, Bill D. Roebuck, Natalie M. Johnson, Thomas W. Kensler, John D. Groopman. Elevated levels of circulating miR-34a-5p and miR-181c-3p during cancer initiation by aflatoxin B1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4448. doi:10.1158/1538-7445.AM2017-4448
Abstract 1049: Combinatorial effects of thymoquinone on the anticancer activity of doxorubicin in adult T-cell leukemia
Authors: Hala Gali-Muhtasib, Isabelle Fakhoury, Maamoun Fatfat, Rasha Mismar, Regine Schneider-Stock
Journal: Cancer Research (2017)

Abstract Doxorubicin (Dox) is a clinically approved drug which suffers from drug resistance and cardiotoxicity. Recent studies have shown that thymoquinone (TQ) in combination with Dox can reduce Dox toxic side effects in vitro as well as in vivo. Both TQ and Dox have shown promising anticancer effects against aggressive adult T-cell leukemia (ATL), however, the anticancer potential of TQ and Dox combination treatment has never been tested against ATL. We hypothesized that co-treatment with TQ could enable the use of lower doses of Dox to achieve similar or enhanced anticancer activity. The effects of TQ and Dox combination on cell death and cell cycle were evaluated by trypan blue and propidium iodide. TUNEL assay was used to investigate the mode of cell death. The levels of reactive species (ROS) were determined using DCFH assay, and mitochondrial membrane potential was measured by rhodamine assay. The regulation of key proteins involved in cell cycle regulation and cell death was determined by Western blot. The results reveal that the human T-lymphotropic virus (HTLV-1) positive HuT-102 cells are more resistant to treatment with Dox alone, than the HTLV-1 negative Jurkat cells. However, treatment with high doses of TQ and low doses of Dox simultaneously, enhances cell death in both cancer cell lines as compared to treatment with Dox alone. TUNEL assay on Jurkat and HuT-102 cells further indicated that the combination of TQ and Dox caused cell death by apoptosis. An increase in ROS production was noted in response to treatment with TQ alone and with TQ and Dox combination in both Jurkat and HuT-102 cells. The oxidative stress; however, was only shown to play a role in the disruption of the mitochondria of Jurkat cells. Similarly, caspase activation was involved in the disruption of the mitochondria of Jurkat cells. The expression levels of key regulatory proteins were modulated in response to treatment with the combination. In conclusion, the combination of TQ and Dox effectively inhibits ATL leukemic cancer cell growth at lower doses of Dox which can potentially lower the side effects of the drug. In vivo studies are still warranted to assess the adjuvant chemotherapeutic potential of TQ in combination with Dox. Citation Format: Hala Gali-Muhtasib, Isabelle Fakhoury, Maamoun Fatfat, Rasha Mismar, Regine Schneider-Stock. Combinatorial effects of thymoquinone on the anticancer activity of doxorubicin in adult T-cell leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1049. doi:10.1158/1538-7445.AM2017-1049
Abstract 4440: New predictive and preventive biomarkers for preclinical hepatocellular carcinoma in Egyptian population by detection of serum miRNAs
Authors: Sara Salama Ghazy, Amira S. Fyala, Ahmed S. Sultan
Journal: Cancer Research (2017)

Abstract The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and carries a poor survival rate. Prognosis, survival and management of patients at risk for developing HCC remain challenging in Egypt and worldwide. Furthermore, poor prognosis of patients with symptomatic (HCC) diagnosed clinically at advanced stages suggests an urgent need for new biomarkers detection that can be used for pre-clinical screening for early detection of premalignant lesions and tumors in high risk to hepatitis C infection. In the present study we used novel formulated anticancer compound(s), combined with or without Sorafenib treatment to exert their antiproliferative effects by eliciting concomitant expression of known or novel biomarkers, including different serum miRNAs, which can be quantitatively analyzed for differences in the levels of metabolites and proteins in the blood and liver tissues of treated HCC xenografts and liver cirrhosis animal models. In addition, circulating miRNAs levels were measured as promising markers in 12 month interval-serum samples that were collected from normal, chronic hepatitis C virus infected patient cohorts at the pre-malignant or pre-clinical stages and liver cirrhotic patients that did not develop cancer. Different serum miRNAs, including miR-21, miR-142, let-7a, let-7b, miR-429 and miR-34a were detected in pre-clinical HCC patients and have the potential to screen for hepatitis C virus infected patients at high risk to develop HCC 12 months after miRNAs detection. Our data of detected serum miRNAs from animal models and patient samples can be used to confirm and correlate histological and histochemical results at various time points with serum or imaging biomarkers, which may have a great promise for the prediction and prevention of HCC in high risk Egyptian populations. Citation Format: Sara Salama Ghazy, Amira S. Fyala, Ahmed S. Sultan. New predictive and preventive biomarkers for preclinical hepatocellular carcinoma in Egyptian population by detection of serum miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4440. doi:10.1158/1538-7445.AM2017-4440
Abstract 3912: Pancreatic cancer cell interaction with platelets impedes cell cycle progression and increases viability
Authors: Andrew C. Cannon, Sushil Kumar, Bradley Hall, Rakesh Bhatia, Rakesh Singh, Surinder Batra
Journal: Cancer Research (2017)

Abstract Background: Metastasizing cancer cells rapidly associate with platelets in circulation, but the nature and functional consequences of this interaction have yet to be fully elucidated. Here we investigated the physical interaction of platelets with pancreatic cancer (PC) cells and the contribution of platelet-derived platelet factor 4 (PF4) mediated signaling in PC cells. Methods: Immunohistochemistry (IHC) and western blot analysis were performed to characterize the expression of PF4 receptor, CXCR3, in 42 Whipple samples and 8 PC cell lines respectively. Physical interaction of human platelets with PC cell lines and its impact on PC cell proliferation in low attachment conditions was analyzed by flow cytometry. Cell viability was assayed by MTT analysis. Immunofluorescence analysis was performed to evaluate PF4 induced autophagy. Results: IHC and western blot analysis in Whipple samples showed CXCR3 expression in 86 percent of the pancreatic tumors and on all the tested PC cell lines respectively. Flow cytometry demonstrated that 24 percent of Capan1 cells interacted with platelets. Interestingly, incubation of platelets with cell-cycle-synchronized Capan1 cells under low attachment conditions inhibited the proliferation of PC cells (~10 percent) at 24 but not 48 hours. This effect was abrogated by pharmacological inhibition of CXCR3 with AMG487. Concurrently, the viability of Capan1 cells grown in low attachment conditions and treated with platelets for 72 hours was greater than that of control and AMG487 with platelets treated groups as assessed by MTT assay. Mechanistic studies suggested that recombinant PF4 augments autophagosome formation as an early event and increases the expression of p21 as a late event. Of note, both LC3 punctation and p21 expression are abrogated by concomitant incubation with PF4 and AMG487. Conclusion: Platelets appear to rapidly interact with cancer cells in suspension. Additionally, in a PF4-CXCR3 signaling dependent manner, platelets inhibit cell cycle progression and increase PC cell viability in low attachment conditions. Cumulatively, these data suggest that platelets aid in the metastatic dissemination of pancreatic cancer cells. Citation Format: Andrew C. Cannon, Sushil Kumar, Bradley Hall, Rakesh Bhatia, Rakesh Singh, Surinder Batra. Pancreatic cancer cell interaction with platelets impedes cell cycle progression and increases viability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3912. doi:10.1158/1538-7445.AM2017-3912
Abstract 5752: Susceptibility of cells from cervical transformation zone to HPV-16 induced immortalization and dysplastic differentiation
Authors: Han Deng, Eric Hillpot, Philomina Yeboah, Sumona Mondal, Craig D. Woodworth
Journal: Cancer Research (2017)

Abstract Persistent infection of high-risk human papillomavirus (HPV) is a major risk factor for cervical cancer. Greater than 90% of these cancers originate in the cervical transformation zone (CTZ), a narrow band of squamous metaplastic epithelium between ectocervix and endocervix. It is unclear why the CTZ has high susceptibility to malignant transformation and few studies have specifically examined cells from this region. We hypothesized cells cultured from human CTZ are uniquely susceptible to cellular immortalization and dysplastic differentiation, two alterations that contribute to malignant development. Primary epithelial cells were cultured from each region of human cervix (ectocervix, endocervix and CTZ) and characterized for expression of differentiation markers to assess their origin. We examined susceptibility of cells from each region to immortalization after transfection with the complete HPV-16 genome or infection of HPV-16 E6/E7 retroviruses. In addition, we evaluated the extent of dysplastic epithelial differentiation in organotypic cultures of HPV16-immortalized cell lines derived from each region of cervix. Our results showed that cells from the CTZ express specific keratin markers (keratin 14 and 18) that confirm their origin. Primary cell cultures from CTZ and ectocervix are more susceptible to immortalization by the HPV16 complete genome or E6/E7 retroviruses. In contrast, preliminary results indicate that HPV-immortalized CTZ and endocervical cells are more susceptible to dysplastic differentiation when maintained in organotypic culture. Our results may help to identify important signal pathways or biomarkers that are unique to cells from CTZ and that can be targeted for improved screening, prevention or therapy. Citation Format: Han Deng, Eric Hillpot, Philomina Yeboah, Sumona Mondal, Craig D. Woodworth. Susceptibility of cells from cervical transformation zone to HPV-16 induced immortalization and dysplastic differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5752. doi:10.1158/1538-7445.AM2017-5752
Abstract 3029: An in vivo role for Argonaute 2 in KRAS driven pancreatic cancer
Authors: Sunita Shankar, Jean Tien, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Ingrid A. Apel, Jiaqi Shi, Chandan Kumar-Sinha, Arul M. Chinnaiyan
Journal: Cancer Research (2017)

Abstract Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we recently identified an interaction between RAS and Argonaute 2 (AGO2), the core component of the RNA silencing machinery exerting translational control of mRNA transcripts. RAS and AGO2 co-sediment and co-localize in intracellular endomembrane bound organelles. The AGO2 N-terminal domain directly binds the KRAS Switch II region, irrespective of GDP/GTP bound to RAS. Functionally, we observed that AGO2 was required for maximal oncogenic KRAS levels and AGO2 knock-down attenuates cell proliferation in mutant KRAS-dependent cells. Intriguingly, AGO2 mediated microRNA processing (RISC activity) was attenuated in cancer cells expressing mutant KRAS compared to those expressing wild type RAS. Yet, these initial investigations using cell line models do not reveal a clear role for AGO2 in KRAS driven oncogenesis. Therefore, we probed the role of AGO2 in the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model driven by oncogenic KRAS. Towards this end, we generated LSL-KrasG12D; Pft1a Cre; AGO2flox/flox (KCA) mice. Preliminary analysis (8-10 weeks of age) suggests that compared to LSL-KRASG12D (KC) mice, homozygous loss of AGO2 results in increased KRAS driven Acinar to Ductal Metaplasia (ADM) phenotype considered as precursors of PanIN (pancreatic intraepithelial neoplasia) and PDAC. This mirrors the phenotype of loss of Dicer in the same model further reinforcing a role for microRNAs in restraining KRAS oncogenic programs. Yet unlike Dicer, loss of AGO2 alone did not cause any gross or histological changes in the development of the mouse pancreata. In an effort to understand the underlying mechanisms that are regulated by AGO2, we also studied the activated levels of a variety of signaling molecules in pancreata obtained from different genotypes. Primary analysis indicates that wild type RAS levels are elevated during AGO2 loss and has a bearing on PDAC initiation. Using both Western blot and Immunohistochemical analyses, we demonstrate a previously unknown and critical role for AGO2 in KRAS-MAPK signaling pathway. Citation Format: Sunita Shankar, Jean Tien, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Ingrid A. Apel, Jiaqi Shi, Chandan Kumar-Sinha, Arul M. Chinnaiyan. An in vivo role for Argonaute 2 in KRAS driven pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3029. doi:10.1158/1538-7445.AM2017-3029
Abstract 4336: Human mesodermal-derived CNS metastasis-associated stromal cells induce a fibrotic response to limit tumor growth
Authors: Christophe Legendre, Gerald C. Gooden, Kyle N. Johnson, Rae Anne Martinez, Mark Bernstein, Jennifer Glen, Jeffrey Kiefer, Aleksander Hinek, Steven A. Toms, Bodour Salhia
Journal: Cancer Research (2017)

Abstract Metastasis to the central nervous system (CNS) remains a major cause of mortality and morbidity in patients with systemic cancer. However, the mechanistic interactions of the neural niche with disseminated tumors cells in CNS metastases (CM) are still poorly understood. To better understand the cross-talk between the neural niche and metastatic tumors, we generated five different patient-derived cell lines (PDCs) originating from surgically resected CM. To assess the genetic and epigenetic characteristics of each PDC, DNA and RNA sequencing, and DNA methylation analysis was performed. Non-tumoral PDCs revealed normal copy number profiles, and retention of germline mutations as seen in patient-matched germline DNA. In contrast, one PDC (CM04) resembled its patient tumor, showing numerous copy number and somatic alterations. RNA-seq and DNA methylation analysis demonstrated that non-tumoral PDCs highly resembled each other, suggestive of a common cell of origin. Additionally, PDCs revealed gene expression signatures associated with cancer associated fibroblasts, epithelial to mesenchymal transition, and mesenchymal stem cells. Further in vivo studies demonstrated that CM04 cells were tumorigenic, whereas non-tumoral PDC (CM08) cells were unable to form tumors in mice. However, CM04:CM08 mixed tumors were significantly smaller than CM04 only tumors and revealed induction of a fibrotic response by immunohistochemistry. These data offer the first evidence that CNS metastasis-associated stromal cells (cMASCs) produce a collagen and fibronectin-rich extracellular matrix constituting a protective host response, which impedes growth of tumor cells. The therapeutic potential of these cells merits further exploration. Citation Format: Christophe Legendre, Gerald C. Gooden, Kyle N. Johnson, Rae Anne Martinez, Mark Bernstein, Jennifer Glen, Jeffrey Kiefer, Aleksander Hinek, Steven A. Toms, Bodour Salhia. Human mesodermal-derived CNS metastasis-associated stromal cells induce a fibrotic response to limit tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4336. doi:10.1158/1538-7445.AM2017-4336