bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2609: A novel MYB-AR cross-talk promoting castration-resistance in prostate cancer
Authors: Srivastava Sanjeev Kumar , Zubair Haseeb , Patel Girijesh K. , Khan Mohammad Aslam , Deshmukh Sachin Kumar , Sing Seema , Andrews Joel , Wang Bin , Carter James E. , Singh Ajay Pratap 
Published: August 2019

Abstract
Progression of prostate cancer from castration-sensitive to castration-resistant disease is a complex process, which likely involves multiple genetic and epigenetic alterations. Here we report a novel mechanism where MYB acts as a novel binding partner of AR enabling its ligand-independent activation to support castration resistance in prostate cancer. MYB and AR interact and co-localize with each other predominantly in the nuclei. Androgen-depletion or enzalutamide treatment does not interfere with MYB-AR interaction, and MYB-overexpressing prostate cancer cells retain AR in the nucleus even when cultured under androgen-deprived condition. Transcriptional activity of KLK3 (an androgen-responsive gene encoding PSA) promoter is increased in MYB-overexpressing cells, while sustained under androgen-depleted condition. In silico analysis identifies a MYB-binding region in KLK3 promoter in close proximity to the AR binding site, and MYB is shown to cooperatively promote AR binding to the KLK3 promoter. MYB-overexpressing prostate cancer cells exhibit greater tumorigenicity when implanted orthotopically and quickly regain growth following castration leading to the poorer survival of mice, compared to those carrying low MYB-expressing prostate tumors. Together, these findings establish a novel and significant role of MYB-AR cross-talk in prostate cancer, which could be exploited for its therapeutic management.
Citation Format: Sanjeev Kumar Srivastava, Haseeb Zubair, Girijesh K. Patel, Mohammad Aslam Khan, Sachin Kumar Deshmukh, Seema Sing, Joel Andrews, Bin Wang, James E. Carter, Ajay Pratap Singh. A novel MYB-AR cross-talk promoting castration-resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2609.
Abstract 2610: The FOXC2 transcription factor promotes growth of melanoma cells in both in vitro and in vivo settings
Authors: Williams Corey J. , Johnson Coleman E. , Bushhouse David Z. , Hargadon Kristian M. 
Published: August 2019

Abstract
Melanoma, a cancer derived from pigment-producing melanocytes of the skin, is a highly aggressive cancer characterized by rapid growth and metastasis. Recent evidence has emerged demonstrating that overexpression of the FOXC2 transcription factor contributes to tumor progression in many cancer types, but the role of FOXC2 in melanoma progression has not previously been studied. Using CRISPR-Cas9 gene editing technology, we have generated and characterized a novel FOXC2 knockout B16-F1 melanoma cell line (B16-F1ΔFOXC2). In comparative in vitro and in vivo studies with wild-type B16-F1 and B16-F1ΔFOXC2 melanomas, we show for the first time that the FOXC2 transcription factor is a critical regulator of melanoma cell growth. The B16-F1ΔFOXC2 melanoma cell line described herein will serve as a useful tool for investigating the function and target genes of FOXC2 in melanoma.
Citation Format: Corey J. Williams, Coleman E. Johnson, David Z. Bushhouse, Kristian M. Hargadon. The FOXC2 transcription factor promotes growth of melanoma cells in both in vitro and in vivo settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2610.
Abstract 2617: FOXC2-associated regulation of melanoma cell adhesion to the extracellular matrix and lymphatic endothelial cells
Authors: Johnson Coleman E. , Williams Corey J. , Hargadon Kristian M. 
Published: August 2019

Abstract
The FOXC2 transcription factor has emerged as a tumor-promoting oncogene in many cancer types. We have recently investigated the impact of Foxc2 gene disruption and FOXC2 overexpression in melanoma on tumor cell adhesion to extracellular matrix (ECM) proteins and lymphatic endothelial cells. We show that melanoma-associated FOXC2 is a critical regulator of tumor cell adhesion to the ECM proteins fibrinogen and fibronectin as well as to lymphatic endothelial cells. These effects on tumor cell adhesion correlate with FOXC2-mediated regulation of the integrins ITGA5 and ITGA9. As changes in cellular adhesion frequently accompany tumor cell transformation and progression, our data suggest that FOXC2 and genes regulated by this transcription factor may play key roles in promoting melanoma invasion and metastasis.
Citation Format: Coleman E. Johnson, Corey J. Williams, Kristian M. Hargadon. FOXC2-associated regulation of melanoma cell adhesion to the extracellular matrix and lymphatic endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2617.
Abstract 2639: Insulin receptor alternative splicing during development and cancer
Authors: Khurshid Safiya 
Published: August 2019

Abstract
It has been shown that alternative splicing of some genes changes during development from embryogenesis to adulthood. Intriguingly, transformation of cells is also often accompanied by a reversion to the embryonic spliced isoforms. Insulin receptor (IN-R) undergoes alternative splicing to produce two isoforms: the full-length IN-RB isoform and the exon 11-skipped IN-RA isoform. The IN-RB isoform encodes a receptor with high affinity for insulin, while the IN-RA isoform has high affinity for both insulin & IGF2 growth hormones. IN-RAexploits the IGF pathway to accelerate growth, proliferation and angiogenesis. It is known that during embryogenesis the IN-R gets spliced to primarily express the INR-A form. Recently, the A isoform has has also been shown to be expressed in certain cancer types. Because the insulin receptor signaling converges on the mTOR/AKTpathway that is one of the most critical pathways for organismal development as well in cancer, it is important to understand the expression of these isoforms and their role in signaling and cellular fate. However, a tissue and a temporal description of the expression of these two isoforms is lacking. Towards this end we have shown that the mouse insulin receptor gene is spliced similarly to the human gene and have used the mouse model to study IR splicing during development. We harvested tissues from mice at different developmental stages (E10, E18, P1, P7, 3 months and 6 months) and performed RT-PCR for the insulin receptor gene. Our data confirmed that the whole embryos at embryonic day 10 (E10) express mostly IN-RA (90%). However, as the embryo develops and we can obtain discrete tissues we are able to detect tissue-specific profiles of IN-Rsplicing. For example, in bone at E18 as well as postnatal day P1 and 7, IN-RBis highly expressed (65%) and decreases to (40%) as the mouse reaches 6 months of age. Likewise, the liver and pancreas, which are primarily involved with metabolic functions, express mostly IN-RB(90%) from postnatal day P1 and into adult hood (6 months). In contrast, when we analyzed IR-splicing in human cancers, we find that in both liver cancer and cancers of the bone (osteosarcoma and Ewing’s sarcoma) there is a shift toward increased levels of the pro-proliferative isoform, IN-RA. We believe that understanding the molecular underpinnings of the splicing regulation during development will provide us with knowledge that will help us better understand the transformation process and how to control it, possibly through splicing corrective therapy.
Citation Format: Safiya Khurshid. Insulin receptor alternative splicing during development and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2639.
Abstract 2641: Transactivation of EGFR and mTOR pathway by H2Sin cancer cells
Authors: Higgins Jillian L. , Kraus Aileen K. , Arruda Dominic T. , Guo Hao , Lautato Mattew , Lautato Christopher , DaCunha Eliana , Chen Ashley , Yao Ricky , Yang Dongqin , Wan Yinsheng 
Published: August 2019

Abstract
Hydrogen sulfide regulates a variety of physiological and pathological processes. Previous studies have suggested that H2S plays a significant role as a secondary messenger in cellular signaling. Interestingly, it has been found that this unique gaseous molecule, or gasotransmitter, is capable of producing both pro- and anti- apoptotic activity in cultured cells. It has been speculated that these gasotransmitters are endogenously generated in mammalian systems through enzymatic catalysis. Our pursuits focus on comparing the effects of H2S on various lines of cancer cells (CaOV3-ovarian cancer cells, A375-melanoma cells, HeLa-cervical cancer cells, and WM 266-4-melanoma cells). Using a water-soluble, slow-releasing H2S donor, GYY4137 (200 μM), we studied how both concentration and time affect cell viability and investigated further whether H2S causes pro- or anti- apoptotic activity. Existing data have indicated that GYY4137 may activate molecular targets, including EGFR, ERK and JNK. We hypothesize that GYY4137 activates mTOR (mammalian target of rapamycin) with result of phosphorylation of S6, leading to either cell death or cell proliferation. By monitoring various proteins through Western blot analysis and confocal microscopy we studied the activation of EGFR/mTOR pathway in response to GYY4137 treatment. Our data showed that the longer the treatment the more prevalent phosphor S6 and phosphor-EGFR are. Noticeably, we observed a significant difference between 15 minutes and 30 minutes, suggesting that GYY4137 has the largest effect after 30 minutes of treatment. We further studied cell growth and viability using MTT assay to investigate the effects of various concentrations of GYY4137 on the cells. Our data indicated that the stronger the concentration is, the lower the cell viability. Similarly, we used Mitotracker ® Red dye to stain for mitochondrial activity in CaOV3 and WM 266-4 cells treated at various time points. Overall, mitochondrial activity increased when cells were exposed to GYY4137, suggesting that H2S may cause anti-apoptotic activity, and instead favor cell growth at the concentration we used. Collectively, our data suggests that the H2S donor, GYY4137 has a significant effect on cell proliferation and survival in several cancerous cells likely mediated by transactivation of EGFR and mTOR pathways.
Note: This abstract was not presented at the meeting.
Citation Format: Jillian L. Higgins, Aileen K. Kraus, Dominic T. Arruda, Hao Guo, Mattew Lautato, Christopher Lautato, Eliana DaCunha, Ashley Chen, Ricky Yao, Dongqin Yang, Yinsheng Wan. Transactivation of EGFR and mTOR pathway by H2Sin cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2641.
Abstract 2642: Antisense oligonucleotide-based induction of dominant-negative variants of STAT3 and EGFR in breast and lung cancer cells
Authors: Subramaniam Prasad , Cartegni Luca 
Published: August 2019

Abstract
The signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including breast and lung adenocarcinomas, where it is known to activate multiple oncogenic pathways and serve as a bypass mechanism in drug resistance. For example, STAT3 is known to be a driver in some basal-like Triple-negative breast cancers (TNBC) and a resistance mechanism to EGFR inhibitors in non-small cell lung cancer (NSCLC). Thus STAT3 has become an attractive target in cancer therapeutics. A naturally occurring alternative splicing variant, STAT3-beta, is truncated and lacks the C-terminal trans-activation domain. Stat3-beta can act in a dominant negative fashion. We recently demonstrated that splice-switching oligonucleotides (SSOs) can be used to induce a shift in endogenous expression from the abundant, oncogenic STAT3-alpha to the truncated dominant-negative STAT3-beta isoform. This leads to decreased cell viability in triple-negative breast cancer cells and to tumor regression in mice, as compared to full STAT3 knock-down or controls. Our aim was to test a panel of next-generation SSOs in order to evaluate their efficacy in basal-like breast cancer cells, which are typically refractory to tyrosine kinase inhibitors. Based on our previous studies, we generated a panel of optimized SSOs targeting STAT3, and assayed the extent of the STAT3 alpha-to-beta switch, at the RNA and protein level, and at their efficacy at eliciting cell apoptosis in MDA-MB-468 TNBC cells, and identified one which show a 5-10 fold improvement of activity in vitro, compared to our previous leading published compound. The optimized STAT3 SSO sequence was also tested in RTK inhibitor-resistant H1975 non-small cell lung cancer cells and was found to be effective in killing the cancer cells as compared to Stat3 knockdown. We also used a similar antisense approach to induce the expression of a dominant-negative variant of the EGFR and tested in combination with our STAT3 SSO. While both the SSO-induced dominant negative variants of EGFR or STAT3 were able to effectively kill lung cancer cells individually, we observed a marked synergistic increase in inhibition when the two compounds where used in combination.
Citation Format: Prasad Subramaniam, Luca Cartegni. Antisense oligonucleotide-based induction of dominant-negative variants of STAT3 and EGFR in breast and lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2642.
Abstract 265: YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance via deregulation of caspase-mediated apoptosis
Authors: Sheu Jim Jinn-Chyuan , Yu Chia-Cheng , Chen I-Hsuan , Korla Praveen , Ko Grace , Chai Chee-Yin , Li Chien-Fong 
Published: August 2019

Abstract
The objective of this study is to characterize the oncogenic roles of a recently identified cancer-associated gene called YWHAZ (also known as 14-3-3 α/ζ ) in urothelial carcinomas of urinary bladder (UCUB). Based on a genomewide study, YWHAZ was found located at the 8q22.3 amplicon and its genetic amplification was predominantly detected in tumors at more advanced stages, muscle-invasive bladder cancer (MIBC). IHC staining confirmed the association of YWHAZ overexpression with higher tumor stages, lymph node/vascular invasion, and mitotic activity. Univariate and multivariate analyses further indicated the prognostic potential of YWHAZ for more aggressive cancer types. Both gene set enrichment analysis (GSEA) and STRING network studies suggest the involvement of YWHAZ in regulating caspase-mediated apoptosis. Ectopic expression of YWHAZ in bladder cells with low YWHAZ levels boosted cells becoming more tolerated toward chemical and ionizing radiation treatments. Gene knockdown by specific shRNA in cells with high YWHAZ levels attenuated the survival activity, resulting in cell growth suppression and cell death. Our data confirmed an essential role of YWHAZ in providing survival signals to sustain cell proliferation during chemo- or radio-therapy. Treatments based on anti-YWHAZ strategies may be beneficial for patients with YWHAZ overexpression.
Citation Format: Jim Jinn-Chyuan Sheu, Chia-Cheng Yu, I-Hsuan Chen, Praveen Korla, Grace Ko, Chee-Yin Chai, Chien-Fong Li. YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance via deregulation of caspase-mediated apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 265.
Abstract 2654: Synergistic inhibition of cancer cell viability and suppression of HIF1α by CDK4 inhibitors and HSP90 inhibitors across cancer types
Authors: Zhao Shuai , Zhou Lanlan , Dicker David T. , El-Deiry Wafik S. 
Published: August 2019

Abstract
Hypoxia is common and hypoxia-inducible factor 1α (HIF1) promotes various aspects of cancer, such as angiogenesis, or metastasis, and confers therapy resistance. Targeting HIF’s is a promising cancer treatment strategy. We previously showed that cyclin-dependent kinase 1 and 4 (CDK1, CDK4) stabilize HIF1α protein in cancer cells (Warfel et al., Cell Cycle, 2013). We also found that CDK activity facilitates HSP90 stabilization of HIF1α and that targeting CDK1 or CDK4/6 and HSP90 simultaneously reduces HIF1α levels and inhibits colorectal cancer (CRC) cell viability. The CDK4/6i palbociclib plus HSP90i ganetespib synergistically inhibit cell viability in HCT116 CRC cells under normoxia and hypoxia, show anti-tumor efficacy in vivo, and reduce both HIF1 and HIF2 levels. To investigate the translational potential of the combination strategy, we explored use of a HSP90i in clinical trials as no HSP90i has been FDA-approved for cancer treatment. Onalespib is a HSP90i undergoing phase I trials for solid tumors and lymphoma. and XL888 is being tested in GI cancer and melanoma. A third HSP90i, TAS116, is under investigation in solid tumors. We found that all these HSP90 inhibitors, in combination with palbociclib, reduce HIF1α levels in CRC cells. Cell viability was inhibited by the combination treatment in a synergistic manner. Similar effects were observed in pancreatic cancer, breast cancer and other tumor types upon treatment with TAS116 and palbociclib. As palbociclib is not the only FDA-approved CDK4/6 inhibitor, we examined the anti-tumor effects of HIF targeting effect using an alternative FDA-approved CDK4/6 inhibitor, abemaciclib. Abemaciclib, in combination with TAS116, decreased HIF1α levels and inhibited cancer cell viability. Our findings demonstrate a class effect towards HIF1α inhibition and cancer cell viability across multiple tumor types from the combination of a CDK4/6i and HSP90i. Ongoing experiments are examining the role of HIF in the sensitivity to the drug combination and the impact of the combined inhibitor therapy on cancer cell migration and invasion. Further clinical translation of this concept is warranted for cancer therapy.
Citation Format: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry. Synergistic inhibition of cancer cell viability and suppression of HIF1α by CDK4 inhibitors and HSP90 inhibitors across cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2654.
Abstract 2656: Regulation of HIF-1a by MDM2 in prostate cancer cells
Authors: Alobid Saad Ebrahim , Rathinavelu Appu 
Published: August 2019

Abstract
MDM2 is an oncogene amplified in approximately 40% of all human prostate carcinomas, and such amplification is correlated very well with aggressive tumor phenotype, distant metastasis, poor treatment outcomes and overall increase in mortality. Interestingly, in cancer cells, hypoxia inducible factor-1alpha (HIF-1α) is activated to facilitate adaptation to the non-conducive tumor microenvironment, through the regulation of downstream genes to ensure tumor survival and progression through modification of protective biological processes. Our previous investigations have outlined a significant role for MDM2 overexpression in regulating HIF-1α under both normoxic and hypoxic conditions in MDM2 expressing LNCaP and MDM2 transfected LNCaP-MST cells, leading to angiogenesis and other detrimental effects. Therefore, our study was aimed to identify how HIF-1α level is regulated in these prostate cancer cells, as a result of MDM2 overexpression, under both normoxic and hypoxic conditions. Analysis of mRNA levels exhibited a significant transcriptional upregulation of HIF-1α in LNCaP-MST compared to LNCaP cells under normoxic condition. Interestingly, targeting the transcriptional machinery with Actinomycin D resulted in a significant downregulation of HIF-1α protein levels also under normoxic conditions. On the other hand, inhibition of proteasomal degradation with MG-132 resulted in further elevation of HIF-1α protein levels in normoxic condition. However, under hypoxic condition, the levels of HIF-1α mRNA seem to be unchanged in both cell lines. In support of these findings, LNCaP-MST cells exhibited a significant downregulation of VHL (Von Hippel-Lindau) levels compared to LNCaP cells under hypoxic condition. The VHL protein typically facilitates polyubiquitination of HIF1α that are marked for proteasomal degradation subsequent to prolyl hydroxylation. So far, our results have confirmed a positive correlation between MDM2 expression and HIF-1α levels under normoxic conditions, while protein degradation may play a significant role during hypoxic conditions. In conclusion, our study provides new evidences that are linking MDM2 overexpression to HIF-1α protein levels in prostate cancer cells under both normoxic and hypoxic conditions, which may be important while considering targeted therapies. (The financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged).
Citation Format: Saad Ebrahim Alobid, Appu Rathinavelu. Regulation of HIF-1a by MDM2 in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2656.