tbuckley/cabot-search huggingface dataset:
Abstract 2317: Prostanoid EP4 receptor induces cleavage of HSP90 via ROS generation in human colon cancer cells
Authors: In Gyeong Chae, Mi-hee Yu, Kyung-Soo Chun
Journal: Cancer Research (2017)

Abstract Prostaglandin E2 (PGE2) has been reported to play critical roles in cell fate decision by interacting with four types of G protein-coupled membrane receptors such as EP1, EP2, EP3 and EP4. We previously reported that EP4 stimulation by treatment with its agonist CAY10598 induced apoptosis via reactive oxygen species (ROS) formation in colon cancer HCT116 cells. Moreover, treatment with CAY10598 diminished the phosphorylation of JAK2 and induced degradation of this oncoprotein, leading to the attenuation of STAT3 activation in HCT116 cells. In the present study, we attempted to delineate the molecular mechanisms underlying the degradation of JAK2 by activation of EP4. HSP90, a member of the heat shock protein family, is a molecular chaperone that supports stability of client proteins, such as, EGFR, MET, Akt and JAK2. HSP90-mediated stabilization/activation of these client proteins contributes to the acquisition of cancer cell hallmarks, including proliferation, survival, angiogenesis and invasion. It has been recently reported that the chaperoning function of HSP90 may be disrupted by post-translational modification induced by oxidative stress. Treatment of human colon cancer HCT116 cells with CAY10598 down-regulated expression of HSP90 client proteins in a concentration- and time-dependent manner and the down-regulation was restored by pretreatment with ROS scavenger N-acetyl cysteine (NAC) or proteasome inhibitor MG132. However, cotreatment with cycloheximide, protein synthesis inhibitor, accelerated the CAY10598-induced degradation of HSP90 client proteins. These data suggest that CAY10598-induced HSP90 client protein degradation may be caused by ROS generation. In renal carcinoma Caki cells, CAY10598 also down-regulated expression of HSP90 client proteins, suggesting that EP4 stimulation may regulate HSP90 activity in colon cancer cells as well as renal cancer cells. We found that HSP90α was cleaved to 40 or 55 kDa, while HSP90β cleaved to 25 kDa by CAY10598 treatment and the cleavage of HSP90α and β was blocked by NAC treatment. Furthermore, EP4 inhibition by treatment with antagonist GW627368x attenuated not only degradation of HSP90 client proteins but also cleavage of HSP90 in CAY105998-treated HCT116 cells. In conclusions, EP4 agonist CAY10598 induces degradation of HSP90 client proteins via ROS-dependent HSP90 cleavage, leading to apoptosis in HCT116 cells. This is a novel mechanism by which EP4 activation induces apoptosis of cancer cells that involved inhibiting HSP90 function. Citation Format: In Gyeong Chae, Mi-hee Yu, Kyung-Soo Chun. Prostanoid EP4 receptor induces cleavage of HSP90 via ROS generation in human colon cancer cells [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 2317. doi:10.1158/1538-7445.AM2017-2317
Abstract 1202: Targeting PIK3C3 to overcome drug resistance resulted from prosurvival autophagy in cancer cells
Authors: CHUN-HAN CHEN
Journal: Cancer Research (2017)

Abstract Autophagy is an important cellular recycling mechanism in which portions of cytosol or organelles are sequestered into a double-membrane structure and delivered to lysosome for degradation. PIK3C3 is the only class III PI3K, which specifically generates phosphatidylinositol 3-phosphate (PtdIns3P). It in turn recruits proteins containing FYVE or PX domains, thereby initiating various complexes at the membranes of endosomes, phagosomes and autophagosomes. Recently, several studies have shown that autophagy is upregulated in cancer cells when exposing to chemotherapy and radiotherapy. Therefore, the rationale of targeting autophagy addiction in cancer was proposed by combining autophagy inhibition with agents that induce autophagy as a pro-survival response to increase their therapeutic efficacy. We stably knocked down PIK3C3 in cancer cell lines and combined with clinical therapeutic agents reportedly induce pro-survival autophagy. Cell viability was examined by MTT assay and combination index was determined by Compusyn software. The autophagy flux was evaluated by detecting protein levels of LC-3II and p62 through western blot analysis. The results showed PIK3C3 knockdown synergistically sensitize the killing effects of gefitinib and gemcitabine in A549 cells and Panc1 cells, respectively. Both of gefitinib and gemcitabine increased autophagy flux, as evidence by the increase of LC3-II and decrease of autophagy substrate, p62. However, the combination of PIK3C3 knockdown and therapeutic agents increased both of the protein levels of LC3-II and p62. These data suggest incomplete autophagy when the function of PIK3C3 was inhibited. The phenomenon was confirmed by bombing autophagy inducer and PIK3C3 inhibitors. Moreover, no appreciable apoptotic cell death was observed. Taken together, our study revealed a potential strategy by targeting PIK3C3 to overcome drug resistance associated with the pro-survival autophagy in cancer. Citation Format: CHUN-HAN CHEN. Targeting PIK3C3 to overcome drug resistance resulted from prosurvival autophagy in cancer cells [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 1202. doi:10.1158/1538-7445.AM2017-1202
Abstract 3897: Novel inhibitor of GBM stem cells targets unique CREB &amp; Myc-mediated self-renewal pathways regulated by CDK5
Authors: Subhas Mukherjee, Carol Tucker-Burden, Changming Zhang, Jun Kong, Monica Chau, Renee Read, Daniel J. Brat
Journal: Cancer Research (2017)

Abstract Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal &amp; multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population &amp; diminishes the differentiation program. To uncover mechanisms relevant to deregulated cell division in human glioma stem cells, we first developed a novel adult Drosophila brain tumor model, 100% enriched with tumor stem cells. Using this model, we performed a suppressor screen for kinases and found brain-specific dCdk5 partially reverses the tumor phenotype. dCdk5 and its human ortholog CDK5 (79% identity) are atypical protein kinases because they do not regulate cell cycle in normal cells, but are critical for neurogenesis &amp; survival of mature neurons. Interestingly, many cancers show overactivation of CDK5 signaling, regulating cell cycle &amp; leading to uncontrolled proliferation. Our analysis of TCGA data shows that IDH wt GBM has significantly high level of CDK5 compared to the IDH wt lower grade glioma. Additionally, we found a strong positive correlation between CDK5 &amp; several stem cell markers in GBM. To date, not much is known about the role of CDK5 in glioblastoma GBM) &amp; glioma stem cell self-renewal. Using patient-derived (GBM) neurosphere cultures &amp; in vivo xenograft tumors in mice, we further demonstrated that a novel pharmaceutical suppressor of CDK5 signaling axis can suppress self-renewal properties through a new CDK5 phosphorylation site on CREB and Myc. Together, our results show that the CDK5 signaling pathway is important for glioma stem cell survival &amp; that suppressing CDK5 could be a novel therapeutic approach to eliminate glioma stem cells. Citation Format: Subhas Mukherjee, Carol Tucker-Burden, Changming Zhang, Jun Kong, Monica Chau, Renee Read, Daniel J. Brat. Novel inhibitor of GBM stem cells targets unique CREB &amp; Myc-mediated self-renewal pathways regulated by CDK5 [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 3897. doi:10.1158/1538-7445.AM2017-3897
Abstract 1215: Apigenin overcomes drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer
Authors: Hye-Sook Seo, Jin Mo Ku, Se Hyang Hong, Hyeong Sim Choi, Jong-Kyu Woo, Bo-Hyoung Jang, Yong Cheol Shin, Seong-Gyu Ko
Journal: Cancer Research (2017)

Abstract Drug resistance in chemotherapy is a major obstacle for successful treatment of cancer. Drug resistance is caused by various reasons including the overexpression of P-glycoprotein (P-gp, MDR1). Development of new useful compound which overcomes drug resistance is urgent. Apigenin, a dietary flavonoid, is reported as an anti-cancer drug in vivo and in vitro. In the present study, we investigated whether apigenin is able to reverse drug resistance using adriamycin-resistant breast cancer cells (MCF-7/ADR) and xenograft mouse model. As a result, apigenin significantly decreased cell growth and colony formation in MCF-7/ADR and its parental MCF-7 cells. This growth inhibition was related with accumulation of subG0/G1 apoptotic population and increase of apoptosis cell number. Apigenin reduced the mRNA expressions of multi-drug resistance 1 (MDR1) and multi-drug resistance associated proteins (MRPs) in MCF-7/ADR cells. Apigenin also down-regulated the expression of P-gp. Apigenin reversed drug efflux from MCF-7/ADR cells resulting in Rho123 accumulation. Inhibition of drug resistance by apigenin is related with suppression of STAT3 signaling pathway. Apigenin decreased STAT-3 activation (p-STAT3) and its nuclear translocation, and inhibited the secretion of VEGF and MMP-9 which are STAT3 target genes. STAT3 inhibitor, JAK inhibitor I and HIF-1α inhibitor decreased cell growth in MCF-7 and MCF-7/ADR cells. In conclusion, apigenin overcomes drug resistance, and this study advances human health. Note: This abstract was not presented at the meeting. Citation Format: Hye-Sook Seo, Jin Mo Ku, Se Hyang Hong, Hyeong Sim Choi, Jong-Kyu Woo, Bo-Hyoung Jang, Yong Cheol Shin, Seong-Gyu Ko. Apigenin overcomes drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast 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 1215. doi:10.1158/1538-7445.AM2017-1215
The contributions of non-numeric dimensions to number encoding, representations, and decision-making factors
Authors: Darko Odic
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. suggest that congruency effects in number perception (biases towards smaller, denser, etc., dots) are evidence for the number's dependence on these dimensions. I argue that they fail to differentiate between effects at three distinct levels of number perception – encoding, representations, and decision making – and that differentiating between these allows the number to be independent from, but correlated with, non-numeric dimensions.
Abstract 2511: The role of lipids metabolism in bladder cancer
Authors: Gang Wang, Rui Cao, Qiangqiang Ge, Yu Xiao, Xinghuan Wang
Journal: Cancer Research (2017)

Abstract Bladder cancer (BCa) is one of the most common malignancy of the urinary tract. Many risk factors for BCa has been demonstrated, including aging, smoking, exposure to chemicals, dietary total cholesterol intake, dietary fatty acids intake, etc. In order to investigate the role of lipids metabolism in bladder cancer, we collected several human BCa tissues and normal bladder tissues to generate an affected pathway network by microarray analysis, and it revealed that glycerolipid metabolism, fatty acid degradation and fatty acid biosynthesis have a close correlation with bladder cancer. Therefore, Simvastatin, one of the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been well-known regarding its effects on rate-limiting step in cholesterol synthesis, was used to treat with BCa cells. We observed that simvastatin could reduce BCa cell proliferation, induce cell cycle arrest at G0/G1 phase and inhibit cell metastasis. Then, the potential alterations of lipids metabolism in bladder cancer cells after simvastatin treatment was investigate by lipidomics analysis. These foundings demonstrate that lipids metabolism plays important role in bladder cancer and some lipids or related enzymes may be the novel targets for bladder cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Gang Wang, Rui Cao, Qiangqiang Ge, Yu Xiao, Xinghuan Wang. The role of lipids metabolism in bladder 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 2511. doi:10.1158/1538-7445.AM2017-2511
Abstract 1417: Expression of BARD1δ induces genetic instability and is associated with cervical carcinogenesis
Authors: Maxim Pilyugin, Pierre-Alain André, Nicole Concin, Gerda Hofstetter, Irmgard Irminger-Finger
Journal: Cancer Research (2017)

Abstract Cervical cancer is always linked to infection with the human papilloma virus (HPV), which causes hyper-proliferation of cervical epithelial cells and neoplasia and cervical cancer. The viral oncoprotein interaction with host tumor suppressor proteins partially explains the uncontrolled proliferation, which ultimately progresses to cervical cancer. However, little is known about the specific factors that promote or inhibit the malignant transformation. Since a portion of HPV infections never evolves into cancer, the identification of discriminatory factors would be an important step towards the development of prognostic and therapeutic tools. Based on this notion, we investigated whether an isoform of BARD1, BARD1δ, which we found frequently expressed in cancer cells, plays a role in the malignant transformation of cervical epithelial cells. Using immunohystochemistry staining on tissue sections and RT-PCR we found that BARD1δ is expressed in proliferating cervical cancer cells, while normal BARD1 is repressed. BARD1 might be a driver of carcinogenesis and might be a critical event in the progression from hyper-proliferating cervical epithelium after HPV infection to cervical cancer. Together, our results show that an isoform of BARD1, BARD1δ, is increasingly expressed in precancerous stages of cervical cancer and the specific inhibition of BARD1δ may represent a novel approach for therapeutic interventions to prevent cervical carcinogenesis after HPV infection. Citation Format: Maxim Pilyugin, Pierre-Alain André, Nicole Concin, Gerda Hofstetter, Irmgard Irminger-Finger. Expression of BARD1δ induces genetic instability and is associated with cervical carcinogenesis [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 1417. doi:10.1158/1538-7445.AM2017-1417
The paradoxical association between pulmonary embolism and COPD
Authors: Laurent Bertoletti
Journal: European Respiratory Journal (2017)

Chronic obstructive pulmonary disease (COPD) is recognised as a moderate risk factor (odds ratio between 2 and 9) for venous thromboembolism (VTE) [1], in the same group as cancer or oral contraceptive therapy. However, as opposed to cancer or the pill, this statistical association may represent a clinical dilemma [2], as COPD and the thoracic clinical presentation of VTE (pulmonary embolism, PE) have similar symptoms. The comprehension of the paradoxical association of COPD and VTE, particularly PE, has improved significantly in recent years [3–8]. COPD is associated with an increased risk of PE, but not of VTE recurrence after anticoagulant therapy cessation <http://ow.ly/3uio30cAtyd>
Pediatric low-grade gliomas: next biologically driven steps
Authors: David T W Jones, Mark W Kieran, Eric Bouffet, Sanda Alexandrescu, Pratiti Bandopadhayay, Miriam Bornhorst, David Ellison, Jason Fangusaro, Michael J Fisher, Nicholas Foreman, Maryam Fouladi, Darren Hargrave, Cynthia Hawkins, Nada Jabado, Maura Massimino, Sabine Mueller, Giorgio Perilongo, Antoinette Y N Schouten van Meeteren, Uri Tabori, Katherine Warren, Angela J Waanders, David Walker, William Weiss, Olaf Witt, Karen Wright, Yuan Zhu, Daniel C Bowers, Stefan M Pfister, Roger J Packer
Journal: Neuro-Oncology (2017)

Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.
Lung Adenocarcinoma as Part of the Li-Fraumeni Syndrome Spectrum
Authors: Olivier Caron, Thierry Frebourg, Patrick R. Benusiglio, Stéphanie Foulon, Laurence Brugières
Journal: JAMA Oncology (2017)

Phuong L. Mai; Payal P. Khincha, MD; Jennifer T. Loud; Rosamma M. DeCastro, CRNP; Renée C. Bremer; June A. Peters; Chia-Ying Liu; David A. Bluemke; Ashkan A. Malayeri; Sharon A. Savage, MD
Abstract 3528:PTCH53as a potential secondary modifier in Li-Fraumeni syndrome
Authors: Anna J. Pan, Benjamin Brew, Lauren Erdman, Anna Goldenberg, David Malkin
Journal: Cancer Research (2017)

Abstract Germline mutations in the TP53 gene have been established as the underlying genetic event in Li-Fraumeni syndrome (LFS), predisposing affected families to a wide spectrum of early onset cancers. Despite rapid progress in elucidating the role of wild-type p53 in maintenance of genome stability, and mutant p53 in cellular transformation, much of the molecular basis underlying LFS remains unclear. Lack of predictability in age of onset, type(s) of cancers, and likelihood of subsequent malignancies prompts further research to examine secondary modifiers on the underlying TP53 genotype. Patched-domain containing 4 (a.k.a PTCHD4 or PTCH53) is a repressor of canonical Hedgehog signaling that is also described to be transcriptionally activated by p53. Furthermore, our group has identified significant hypomethylation at the PTCH53 locus in a mutant TP53 LFS cohort, compared to TP53 wildtype carriers. These results suggest a potential role of PTCH53 in modifying LFS phenotype. The study examines the expression profile of PTCH53 in the presence of different germline TP53 mutations using primary LFS patient-derived fibroblasts, and aims to elucidate the functional role of PTCH53. PTCH53 transcriptional expression was assessed using digital droplet PCR in 10 LFS non-transformed fibroblast cell lines representing a spectrum of heterozygous germline TP53 mutations. Our data demonstrate that PTCH53 expression indeed depends on TP53 genotype where different TP53 mutations correspond with varied PTCH53 mRNA levels. Nonetheless, mutant TP53 fibroblasts have overall lower PTCH53 transcripts compared to wild-type TP53 fibroblasts. Fold-change increase in PTCH53 expression was detected upon doxorubicin and γ-irradiation induced activation of the p53 protein. These results suggest that induction of p53 via DNA damage activates a signaling cascade involving PTCH53 up-regulation. Further experiments will examine the functional consequences to PTCH53 de-regulation via shRNA knockdown and CRISPR knockout models, and will examine possible modifying effects of PTCH53 on the functional phenotype (cell viability, colony formation and migration potentials) of cell lines harboring different p53 mutants. Elucidating the functional profile of PTCH53 in the context of Li-Fraumeni syndrome will contribute to understanding the complex molecular basis underlying this cancer predisposition syndrome. Citation Format: Anna J. Pan, Benjamin Brew, Lauren Erdman, Anna Goldenberg, David Malkin. PTCH53 as a potential secondary modifier in Li-Fraumeni syndrome [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 3528. doi:10.1158/1538-7445.AM2017-3528