bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4380: LSR promotes cell proliferation and migration subsequent to uptake of fatty acid in epithelial ovarian cancer
Authors: Hiramatsu Kosuke , Serada Satoshi , Fujimoto Minoru , Ueda Yutaka , Kimura Tadashi , Naka Tetsuji 
Published: August 2019

Abstract
Background Previously, we identified lipolysis-stimulated lipoprotein receptor (LSR) as a new therapeutic target of epithelial ovarian cancer (EOC), and we reported anti-cancer effect of our newly developed monoclonal antibody (mAb) against LSR-positive EOC in vitro and in vivo. We also demonstrated that LSR took in triglyceride-rich protein and contributed cell proliferation, however, lipid metabolic pathway via LSR is still unclear. Thus, we aimed to reveal the function of LSR on lipid metabolism in EOC cells.
Methods We investigated the activation of beta-oxidation, ATP production, cell proliferation and cell migration via LSR after administration of fatty acid (FA) using LSR-positive EOC cells and LSR-knockout EOC cells. Moreover, we also investigated anti-cancer effect of our anti-LSR mAb against lipid metabolism via LSR.
Results In LSR-positive EOC cells, FA administration increased intracellular lipid accumulation. In glucose restricted environment, LSR promoted FA uptake and promoted ATP production (p &lt; 0.05). In addition, FA promoted cell proliferation and cell migration in LSR-positive EOC cells (p &lt; 0.05). These results suggest that LSR promoted FA uptake in glucose restricted environment and also promoted lipid metabolism including beta-oxidation, TCA cycle and electron transport system leading to ATP production. Finally, our anti-LSR mAb inhibited these lipid metabolic pathways (p &lt; 0.05).
Conclusions Fatty acid uptake via LSR in glucose restricted environment contributed to cell proliferation and migration subsequent to activation of lipid metabolism, and anti-LSR mAb inhibited these processes. LSR might contribute to cancer spread and metastasis of EOC.
Citation Format: Kosuke Hiramatsu, Satoshi Serada, Minoru Fujimoto, Yutaka Ueda, Tadashi Kimura, Tetsuji Naka. LSR promotes cell proliferation and migration subsequent to uptake of fatty acid in epithelial ovarian 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 4380.
Abstract 4393: Integrative proteomic analysis of prostate cancer reveals distinct regulation of RNA binding proteins during disease progression
Authors: Scaravilli Mauro , Kohvakka Annika , Ruusuvuori Pekka , Afyounian Ebrahim , Nykter Matti , Visakorpi Tapio , Latonen Leena 
Published: August 2019

Abstract
To understand the etiology of the disease, and to find novel and more specific drug targets, the driver mutations and expressional changes in prostate cancer have been examined through extensive genomic and transcriptomic characterization. Although significant insight has been gained through these efforts, it is clear that not all molecular alterations influencing the tumor outcome can be captured through these approaches, and that a comprehensive understanding of the molecular events in cancer require thorough investigation of the proteome.
To understand the functional consequences of genetic and transcriptional aberrations in prostate cancer, we aimed to reveal the proteomic changes during disease formation and progression. We performed high throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration resistant prostate cancer (CRPC). We performed an integrative analysis of the proteomic data with gene copy number, DNA methylation, and RNA expression data from the same samples. Furthermore, proteomic events correlating with the androgen receptor (AR) status of the tumors were analysed.
We uncovered previously unrecognized molecular and pathway events and several novel AR-associated events in the prostate cancer proteomes to study further. We found significant changes in expression of RNA-binding proteins during disease formation and progression. Examining the relationship of RNA binding proteins at the RNA and protein expression level reveal that while many RNA binding proteins exhibit correlation between the expression levels, some seem regulated at the posttranslational level. Two RNA binding proteins, TDP-43 and FUS, which regulated at the protein, but not at RNA level during prostate cancer progression, show opposite behavior during disease progression and correlation with AR status of the tumors. In cultured prostate cancer cell models, we show that these proteins have specific, but divergent interactions with AR at the RNA and protein levels, and that they contribute differentially to AR activity-mediated responses. Thus, these proteins may significantly contribute to prostate cancer molecular evolution and may pinpoint possible targetable pathways in future prostate cancer therapy.
Citation Format: Mauro Scaravilli, Annika Kohvakka, Pekka Ruusuvuori, Ebrahim Afyounian, Matti Nykter, Tapio Visakorpi, Leena Latonen. Integrative proteomic analysis of prostate cancer reveals distinct regulation of RNA binding proteins during disease progression [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 4393.
Abstract 4403: Regulation of SATB2 via miR-31 in Ni-induced malignant cell transformation
Authors: Chen Qiao Yi , Zhu Yusha , Jordan Ashley , Li Jinquan , Sun Hong , Kluz Thomas , Costa Max 
Published: August 2019

Abstract
The special AT-rich DNA binding protein (SATB2) is a nuclear matrix associated protein and an important transcription factor for biological development, gene regulation, and chromatin remodeling. Under normal circumstances, SATB2 is not expressed in most cells, including epithelial cells of the lung. However, aberrant regulation of SATB2 has been found in various types of cancers including lung, colon, prostate, breast, gastric, and liver. Emerging studies have linked the possible role of SATB2 in carcinogenic metal-induced cell transformation. In fact, our previous microarray analysis showed that SATB2 is strongly induced in Ni-transformed cells. As an IARC Class I Human Carcinogen, there is well-established link between chronic nickel exposure and lung cancer; however, despite of considerable research efforts in regards to the epigenetic mechanisms, little is known about the role of microRNAs in Ni-induced carcinogenesis. As post-transcriptional regulators, miRNAs have great importance in maintaining normal cellular development. In particular, miR-31 is one of the most abundant types of miRNAs and commonly studied in disease development, including cancers of the lung, breast, and liver. Previous studies have shown the miR-31 can directly target the homeobox gene SATB, and here we report that miR-31 is capable of regulating SATB2 in Ni-induced tumorigenesis. First, our results confirmed that knocking down SATB2 in Ni-transformed BEAS-2B cells via shRNA significantly reduced the rate of migration, anchorage-independent growth. Notably, compared to scramble control shRNA transfected cells, SATB2 knockdown cells did not generate tumor growth in mice xenograft model. These results highlight the oncogenic role of SATB2 in cell transformation. In addition, our data indicate that both acute Ni-treated and Ni-transformed cells demonstrated significant reduction in miR-31 expression. Furthermore, we show that overexpressing miR-31 in Ni-transformed cells reduced rates of migration, anchorage-independent growth, and cellular invasion, indicating the importance of miR-31 in Ni-induced BEAS-2B cell transformation. Together, our results provide a novel mechanistic pathway for Ni-induced carcinogenesis, and add to the pool of existing research on the implications of SATB2 and miR-31 in tumorigenesis.
Citation Format: Qiao Yi Chen, Yusha Zhu, Ashley Jordan, Jinquan Li, Hong Sun, Thomas Kluz, Max Costa. Regulation of SATB2 via miR-31 in Ni-induced malignant cell transformation [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 4403.
Abstract 4412: Piperine enhances the efficacy of 5 FU against liver cancer
Authors: Anwanwan David , Singh Santosh Kumar , Lillard James W. , Mishra Manoj K. , Singh Rajesh 
Published: August 2019

Abstract
Liver cancer is one of the most devastating malignancies. Hepatocellular carcinoma (HCC) accounts for &gt;90% of primary liver malignancies and is the third-leading cause of cancer-related deaths worldwide. Systemic chemotherapy is one of the most important treatment modalities for advanced HCC. Unfortunately, long-term treatment acquired resistance in HCC due to the activation of drug efflux pumps. A natural compound in combination with chemotherapeutic drugs is a potential approach to combat the side effects. In this study, we have demonstrated whether piperine (natural compound) could increase the effect of 5-FU in HCC cells. The cell viability (MTT) assay was performed to determine the optimal IC50 values of Piperine, 5-FU alone and in combination. Immunofluorescence study confirmed the effectiveness of combined drug; dead nuclei were found more within the cells treated by the combination compared to piperine or 5-FU alone. The combined drug treatment was most effective in inhibiting proliferation and inducing apoptosis; accordingly, it showed noticeable increases in pro-apoptotic (BAK, BID), PARP and decreases in anti-apoptotic genes (BCL-XL) gene in a western blot and RT-PCR analysis. Further, in SK-HEP-1 cells, the combination upregulated the expression of cell cycle inhibitors (p21WAF1/CIP1, p27KIP), which, in turn, inhibited the expression of CDK2/ Cyclin D1 complex. Therefore, it blocks the transition of cells into G0/G1 to S phase. Taken together, we observed that the combination of 5-FU and Piperine resulted in a significant cytotoxicity and apoptosis as compared to alone. Our results suggest that piperine can be a potential agent in enhancing the efficacy of 5-FU in liver cancer treatment. These finding highlights the promising role of natural bioactive compounds and provides the rationale for further transitional researches.
Citation Format: David Anwanwan, Santosh Kumar Singh, James W. Lillard, Manoj K. Mishra, Rajesh Singh. Piperine enhances the efficacy of 5 FU against liver 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 4412.
Abstract 4433: Novel and highly selective CDK9 inhibitors suppress proliferation of triple negative breast cancer (TNBC) cells in vitro
Authors: Winter Jean M. , Mustafa Ebtihal H. , Wang Shudong , Selth Luke A. , Hickey Theresa E. , Tilley Wayne D. 
Published: August 2019

Abstract
This study evaluates the efficacy of two newly developed selective CDK9 inhibitors (CDK9i) across a panel of TNBC cell lines. MDA-MB-453, MFM-223, MDA-MB-468 and MDA-MB-231 TNBC cells were treated with increasing concentrations of two novel and highly selective CDK9 inhibitors and the effect on proliferation, apoptosis and expression of CDK9 targets determined. MDA-MB-453 and -468 cells showed significant growth inhibition with as little as 150nM of CDK9i, evident 3 days after commencement of treatment. Both MDA-MB-231 and MFM-223 cells were less sensitive to the CDK9 inhibitors, with MDA-231 cells requiring at least 300nM to suppress growth. MFM-223 cells did not demonstrate any growth inhibition after 7 days of culture with CDK9i concentrations up to 1.2uM. Protein expression of CDK9 targets, including RNA Polymerase II (RNAPII), phosphorylated-RNAPII, the proto-oncogene C-MYC, and apoptotic marker cleaved caspase-3, were examined by Western blot after optimal CDK9i exposure across each cell line. CDK9i suppressed phosphorylated-RNAPII, but not total RNAPII, indicative of targeted CDK9 inhibition. The master transcription factor C-MYC, which is highly expressed in TNBC, was downregulated, and cleaved-caspase-3 was upregulated with CDK9i treatment. These data demonstrate cell specific efficacy of novel CDK9 inhibitors in cell line models of TNBC via transcriptional suppression of proto-oncogenes and upregulation of apoptotic pathways. Future studies will identify molecular markers of response to CDK9 inhibition and evaluate these novel inhibitors in TNBC patient derived xenografts.
Citation Format: Jean M. Winter, Ebtihal H. Mustafa, Shudong Wang, Luke A. Selth, Theresa E. Hickey, Wayne D. Tilley. Novel and highly selective CDK9 inhibitors suppress proliferation of triple negative breast cancer (TNBC) cells in vitro [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 4433.
Abstract 4435: Molecular mechanism of a novel covalent allosteric inhibitor of SUMO E1 activating enzyme
Authors: Lyu Zongyang , Yuan Lingmin , Williams Katelyn M. , Atkison James H. , Olsen Shaun K. 
Published: August 2019

Abstract
Post-translational modification of proteins by ubiquitin and ubiquitin-like proteins (collectively termed Ubls) proceeds through the sequential interactions and activities of parallel cascades of enzymes that are structurally and mechanistically related. E1 enzymes initiate Ub/Ubl conjugation cascades by catalyzing the ATP-dependent activation and transfer of their cognate Ub/Ubl to E2-conjugating enzymes, which then function with an array of E3 ligases to catalyze the formation of an isopeptide bond linking the Ub/Ubl to target proteins. Aberrations in Ub/Ubl modifications are associated with the pathogenesis of a wide range of life-threatening diseases, which has resulted in several Ubl E1 enzymes emerging as attractive targets for the development of small molecule therapeutics. We present the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a small molecule representing a new class of Ubl E1 enzyme inhibitor. The structure reveals that the covalent allosteric inhibitor targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that inhibitor binding is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. Altogether our studies provide the molecular mechanisms of inhibition SUMO E1 specificity and establishes a framework for the development of molecules targeting other Ubl E1s at a newly discovered cryptic allosteric site.
Supported by NIH R01GM115568, F30CA216921, T32CA193201, and a Hollings Cancer Center Postdoctoral Fellowship.
Citation Format: Zongyang Lyu, Lingmin Yuan, Katelyn M. Williams, James H. Atkison, Shaun K. Olsen. Molecular mechanism of a novel covalent allosteric inhibitor of SUMO E1 activating enzyme [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 4435.
Abstract 4443: Targeting E3 ligase PJA1 via TGF-β pathway in hepatocellular carcinoma
Authors: Ohshiro Kazufumi , Chen Jian , Jogunoori Wilma , Deng Chu-Xia , Mishra Bibhuti , Li Shulin , Mishra Lopa 
Published: August 2019

Abstract
Background: RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown for specific pathways such as TGF-β/Smad signaling that when disrupted, drive hepatocellular carcinoma (HCC). We, therefore, analyzed the TCGA database for the TGF-β pathway associated 22 E3 ligases, and identified mRNA alterations in 55% of tumors, most prominently for UCHL5 (16.4%), PJA (12.7%), WWP2 (11.8%), SKP2 (9.1%), SMURF1 and SMURF2 (8.2 and 9.1%, respectively), ITCH (6.4%) and KEAP1 (6.4%). We previously uncovered increased PJA1 expression with loss of TGF-β substrates Smad3 and β2SP in TGF-β deficient mice (β2SP+/-/Smad3+/- mice), which spontaneously develop characteristics of a human stem cell syndrome, and HCC by 12-15 months. Here, we report PJA1 oncogenic function in HCC progression. HCC.
Methods & Results: (1) Analyses of primary HCC datasets (91 cases) reveal increased PJA1 correlates with decreased levels of TGF-β/Smad3 and their regulated genes including Smad8 and TGFBR3. (2) To better understand the implications of PJA1-mediated deregulation of Smad3-promoted transcription in HCC, we compared transcriptomes of HepG2 cells silenced by PJA1 shRNA or treated with TGF-β: 1,584 genes including c-FOS were co-up-regulated and 1,279 genes including TERT were co-down-regulated. PJA1 expression in HCC was negatively associated with c-FOS and SERPINE1 expression. (3) PJA1 interacts with the Smad3 MH2 and Linker domains and multiple domains of β2SP to promote ubiquitin-mediated phosphor-Smad3 degradation in a TGF-β dependent manner, resulting in decreased TGF-β target gene activity. (4) We found that PJA1 expression in HCC is negatively associated with c-FOS and SERPINE1 expression. (5) Overexpression of a RING-domain-deleted PJA1 mutant reduced the proliferation rate in HCC cells and PJA1 knockdown significantly decreased anchorage-independent growth and tumorigenicity of HCC cells. (6) Our results also demonstrate that PJA1 promotes liver cancer stem cell formation in Smad3+/- mice.
Conclusions: This study demonstrates that loss of expression of β2SP and Smad3 through PJA1 could play an important role in HCC progression and that PJA1 is a potential novel therapeutic target for this lethal disease.
Citation Format: Kazufumi Ohshiro, Jian Chen, Wilma Jogunoori, Chu-Xia Deng, Bibhuti Mishra, Shulin Li, Lopa Mishra. Targeting E3 ligase PJA1 via TGF-β pathway in hepatocellular carcinoma [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 4443.
Abstract 4450: Novel transducer array layouts to optimize the treatment of multiple brain metastases with tumor treating fields
Authors: Yesharim Ofir , Naveh Ariel , Bomzon Ze'ev 
Published: August 2019

Abstract
Introduction:
Tumor Treating Fields (TTFields) is an antimitotic cancer treatment approved for the treatment of Glioblastoma Multiforme (GBM). TTFields are delivered using 2 pairs of transducer arrays positioned on the shaved scalp of the GBM patient to optimize the TTFields dose delivered to the tumor. This results in an increased dose of TTFields to the affected tumor region, whilst reducing the intensity of the fields to other regions. Brain metastases, or secondary brain tumors, occur in 10 to 30 percent of adults with cancer. Cancer types most likely to cause brain metastases are lung, breast, colon, kidney and melanoma. When using TTFields to treat brain metastases, it may be desirable to deliver TTFields at therapeutic intensities to the entire brain, in order to treat multiple rather than a single lesion. We investigated novel transducer array layouts designed to deliver a uniform distribution of TTFields to the entire brain.
Methods
Computer simulations were used to calculate the field distributions generated by different array layouts. The simulations utilized a realistic computerized head model of a 40+ years old human male prepared in-house from a T1 MRI series. Using Sim4Life v3.0 (ZMT Zürich), we simulated the delivery of TTFields using pairs of array layouts placed at different locations on the head and neck. To analyze the field distributions, the brain was divided into five regions: (1) the cerebellum, brain stem and other infra-tentorial anatomical regions; and (2-5) the four quadrants of the cerebrum. The mean and median field intensities in the five regions generated by each layout were calculated and compared.
Results
Median intensities between 1.5 V/cm to 1.7 V/cm within all regions were achieved using a layout in which one pair of arrays was placed on the right temple and left scapula, while the second pair was placed on the left temple and right scapula. This layout yielded a uniform intensity distribution within the brain.
Conclusion
We have identified a novel TTFields array layout that could potentially be used to treat the entire brain with sufficiently high intensity to treat for brain metastases. The ongoing Phase 3 METIS study [NCT02831959 is investigating radiosurgery with TTFields for 1-10 brain metastases from non-small cell lung cancer.
Citation Format: Ofir Yesharim, Ariel Naveh, Ze'ev Bomzon. Novel transducer array layouts to optimize the treatment of multiple brain metastases with tumor treating fields [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 4450.
Abstract 4452: GNE-0011, a novel monovalent BRD4 degrader
Authors: Blake Robert A. 
Published: August 2019

Abstract
The bromodomain and extra-terminal (BET) family of proteins (BRD2, 3, 4 and T) has been the focus of an emerging paradigm in drug mechanism of action, whereby a drug is designed to trigger the proteolytic degradation of the target protein. The current design of protein degraders is typically based on bivalent molecules consisting of a ligand for the target protein and a ligand for a ubiquitin ligase (such as VHL, CRBN or XIAP). The degrader causes the association of the target protein with the E3 ubiquitin ligase and its subsequent ubiquitination and degradation. Due to their bivalent design such drugs typically have a higher molecular weight than classic small molecule drugs and may present some non-ideal properties as drugs. An alternative strategy for designing drugs that act through the degradation of the target protein is exemplified by the group of drugs termed SERDs (selective estrogen receptor degraders), for example fulvestrant. The molecular structures of SERDs are typically designed around an estrogen receptor ligand and a “degradation tail”, whose presence results in the degradation of the estrogen receptor. We will discuss the development of GNE-0011, which represents a novel class of monovalent BRD4 degrader that uses a “degradation tail” strategy.
Citation Format: Robert A. Blake. GNE-0011, a novel monovalent BRD4 degrader [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 4452.