bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1981: Histone demethyalase JMJD1A promotes the DNA damage response of prostate cancer cells
Authors: Fan Lingling , Peng Guihong , Sahgal Natasha , Fazli Ladan , Gleave Martin , Zhang Yuji , Hussain Arif , Rassool Feyruz , Qi Jianfei 
Published: July 2016

Abstract
DNA damage is a common feature of prostate cancer (PCa) therapies (e.g. radio-, chemo- and androgen deprivation therapies). Thus, the DNA damage response (DDR) is a key factor in determining the therapeutic response of PCa patients. JMJD1A regulates gene expression by demethylating H3K9. Here, we identified a new role for JMJD1A in the DDR of PCa cells. Inhibition of JMJD1A led to increased r-H2AX foci (marker for the double strand DNA breaks) in the non-irradiated cells, and the delayed clearance of r-H2AX foci in the irradiated cells. JMJD1A knockdown in PCa cells inhibited the DNA strand break repair in the reporter assays. We further found that phosphorylation and ubiquitination were key modifications that regulate the activity of JMJD1A in the DDR. Ectopic expression of the mutant JMJD1A at the phosphorylation or ubiquitination site attenuated the expression of DNA repair factors, DNA strand break repair, and PCa cell proliferation under irradiation and androgen deprivation conditions. Our results suggest that targeting JMJD1A may sensitize the response of PCa to the major anti-PCa therapies.
Citation Format: Lingling Fan, Guihong Peng, Natasha Sahgal, Ladan Fazli, Martin Gleave, Yuji Zhang, Arif Hussain, Feyruz Rassool, Jianfei Qi. Histone demethyalase JMJD1A promotes the DNA damage response of prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1981.
Abstract 201: Tribble 3 as integrator of metabolic stresses during lung cancer progression
Authors: Almiman Abeer , Adom Jamila , Guo Yande , Wang Jiuhui , Nie Daotai 
Published: July 2016

Abstract
Introduction: Tribbles pseudokinase 3 (TRIB3) has been identified as a stress related gene. Recent studies reported the increased expression of TRIB3 in cancers and its correlation with the poor prognosis in cancer patients. However, other studies suggest TRIB3 as a tumor suppressor due to its inhibitory activities toward PI3K/Akt and Mek-Erk signaling. In the present study, we aim to investigate the expression of TRIB3 in lung cancer cells and whether it plays a role in lung cancer progression and responses toward chemotherapy.
Methods: TRIB3 expression was determined by RT-PCR and Western blot. A lentiviral vector was used to overexpress TRIB3 in lung cancer cells. Small hairpin RNA constructs targeting TRIB3 were used to deplete TRIB3 expression. A CRISPR-CAS9 construct with guiding sequence matching to TRIB3 gene was used to knock out its expression. Cell proliferation, survival, and migration were determined using standard techniques.
Results: Through in silico analyses, we found that high level of TRIB3 RNA was associated with poor survival of lung cancer patients. In lung cancer cells (NCI-H358), TRIB3 expression was markedly stimulated during metabolic stresses or ER stresses. Overexpression of TRIB3 in cells led to decreased cell proliferation and increased arrest at G0/G1 phase, even when the cells were not under overt metabolic stresses. RT-qPCR analyses of cell cycle proteins revealed an upregulation of p27, a CDK inhibitor, in cells overexpressing TRIB3. Overexpression of TRIB3 reduced Akt phosphorylation at threonine 308. Depletion or knockout of TRIB3 led to increased cell growth but cells became more sensitive to stressors, leading to increased apoptotic cell death.
Conclusion: Our study reveals complex roles of TRIB3 in lung cancer progression. Induced by metabolic stresses, TRIB3 can block cell cycle progression through p27 in adaptive responses. Further studies are needed to determine whether and how TRIB3 functions as a metabolic gatekeeper during lung cancer progression.
Citation Format: Abeer Almiman, Jamila Adom, Yande Guo, Jiuhui Wang, Daotai Nie. Tribble 3 as integrator of metabolic stresses during lung cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 201.
Abstract 207: Regulation of mitochondrial biogenesis in primary human clear cell renal cell carcinoma cells
Authors: Nilsson Helén Å. , Johansson Martin E. 
Published: July 2016

Abstract
Clear cell renal cell carcinoma, ccRCC, is the most prevalent type of kidney cancer. In over 90% of ccRCCs the tumor suppressor protein von Hippel Lindau is inactivated, leading to a pseudohypoxic phenotype with vast effects on angiogenesis as well as energy metabolism. In accordance with the Warburg effect, aerobic glycolysis increases, while mitochondrial oxidative phosphorylation is decreased.
We have previously published data showing that also the number and activity of mitochondria is strikingly reduced in primary human ccRCC cells compared to normal kidney epithelial cells. This was not seen in any of the established RCC cell lines included in the study. We are now continuing these studies by investigating the regulation of mitochondrial biogenesis in primary human ccRCC cells, and how the number and activity of mitochondria influences the tumorigenic properties of these cells.
RNA has been isolated from ccRCC tissue areas identified as mitochondria high or low. The expression profile in these samples will be analyzed by RNA sequencing.
Human primary ccRCC cells obtained from patient nephrectomies are kept in culture and the regulation of mitochondrial biogenesis in these cells is investigated. How the mitochondrial content affects tumorigenic properties such as proliferation, migration and resistance to apoptosis is also investigated.
Preliminary data indicate that primary ccRCC cells have an absent or severly limited capability to increase the number of mitochondria on metabolic demand, and that the regulation of mitogenesis is defective.
These results point towards a malfunctioning energy sensing and mitochondrial biogenesis in ccRCC cells that might be part of the explanation to the very low mitochondrial content in these cells.
Citation Format: Helén Å. Nilsson, Martin E. Johansson. Regulation of mitochondrial biogenesis in primary human clear cell renal cell carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 207.
Abstract 21: The mTORC2 target Akt is regulated in response to glutamine metabolite levels
Authors: Jacinto Estela , Moloughney Joseph , Kim Peter K. , Vega-Cotto Nicole M. , Wu Chang-Chih , Lynch Thomas , Zhang Sisi , Adlam Matthew , Guntaka Sai , Chou Po-Chien , Rabinowitz Joshua D. , Werlen Guy 
Published: July 2016

Abstract
Highly proliferating cells are particularly dependent on glucose and glutamine for bioenergetics and to fuel biosynthesis of macromolecules. The signals that respond to the fluctuations of these nutrients and how they control metabolic pathways remain poorly understood. mTOR, as part of mTOR complex 1 (mTORC1), responds to amino acids and plays a central role in metabolism. On the other hand, little is known on how mTORC2, consisting of the core components mTOR, rictor, SIN1 and mLST8 is regulated and its metabolic functions. The phosphorylation of the mTORC2 substrate, Akt, is enhanced in cancer cells, suggesting that mTORC2 becomes deregulated during tumorigenesis. Here we found that the activity of mTORC2 is enhanced by diminishing glutamine-derived metabolites. mTORC2 activity is required by glutamine-requiring biosynthetic pathways such as the hexosamine biosynthetic pathway (HBP). Acute nutrient withdrawal augments Akt phosphorylation but does not affect GFAT1 expression. However, extreme starvation that eventually depletes intracellular glutamine metabolites inactivates mTORC2 and downregulates GFAT1 expression. Thus, while mTORC1 senses glutamine abundance to promote anabolism, mTORC2 responds to declining glutamine catabolites in order to restore metabolic homeostasis. Our findings uncover the role of mTORC2 in metabolic reprogramming and provide insights on more effective therapeutic strategies for glutamine-dependent tumors.
Citation Format: Estela Jacinto, Joseph Moloughney, Peter K. Kim, Nicole M. Vega-Cotto, Chang-Chih Wu, Thomas Lynch, Sisi Zhang, Matthew Adlam, Sai Guntaka, Po-Chien Chou, Joshua D. Rabinowitz, Guy Werlen. The mTORC2 target Akt is regulated in response to glutamine metabolite levels. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 21.
Abstract 2102: Targeting mTOR downstream of LIN28 in atypical teratoid rhabdoid tumors promotes apoptosis and suppresses tumorigenicity
Authors: Rubens Jeffrey , Price Antoinette , Orr Brent , Eberhart Charles , Raabe Eric 
Published: July 2016

Abstract
LIN28 is a somatic cell reprogramming and stem cell factor that binds to and regulates RNA involved in growth, invasion and metabolic genes. We have previously shown that LIN28 is upregulated in atypical teratoid rhabdoid tumors (AT/RT) and contributes to the aggressive nature of these tumors. One of the canonical downstream targets of LIN28 is the mTOR pathway. We hypothesized that AT/RT tumorgenicity is dependent on mTOR signaling downstream of LIN28 and inhibition of this pathway would disrupt tumor growth. We found that primary human AT/RT samples have high expression of the mTOR pathway as determined by immunohistochemistry staining for P-S6 and P-AKT Ser473 (21% of tumors with 2+ P-S6 staining; 87% with 2+ p-AKT staining). The dual TORC1/2 inhibitor MLN0128 has good brain penetration and is currently being tested in phase I clinical trials. Treatment of AT/RT cell lines with MLN0128 inhibits TORC1/2 targets in vitro and suppresses cell proliferation at 100nM concentration in multiple AT/RT cell lines (MTS assay for BT12 p&lt;0.005 vs DMSO control; BT37 p = 0.006 vs DMSO control; and CHLA-06 p&lt;0.005 vs DMSO control by t-test). MLN0128 also slows cell proliferation via BrdU assay (BT12 p&lt;0.005 vs DMSO control; BT37 p&lt;0.005 100nM vs DMSO control; CHLA-06 p&lt;0.005 100nM vs DMSO control by t-test) and induces apoptosis measured by Western Blot for cleaved PARP and cleaved caspase 3 assay (BT12 p&lt;0.005 100nM vs DMSO; BT37 p&lt;0.005 100nM vs DMSO; CHLA-06 p = 0.007 100nM vs DMSO by t-test). MLN0128 induces apoptosis synergistically with cisplatin, which is the backbone of conventional AT/RT therapy (CC3 assay BT37 p&lt;0.005 vs DMSO by t-test) and slows cell growth (MTS assay BT37 p&lt;0.005 vs DMSO control by t-test). MLN0128 treatment of AT/RT xenograft mouse models extends overall survival from a median of 23 days to 39 days (Log-rank test p = 0.002). Targeting the mTOR pathway with MLN0128 leads to potent in vitro and in vivo activity against AT/RT and can be combined with conventional chemotherapy to provide an important survival benefit. MLN0128 may be a candidate for future clinical trials to treat this deadly tumor.
Citation Format: Jeffrey Rubens, Antoinette Price, Brent Orr, Charles Eberhart, Eric Raabe. Targeting mTOR downstream of LIN28 in atypical teratoid rhabdoid tumors promotes apoptosis and suppresses tumorigenicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2102.
Abstract 2105: c-Met hyperactivation is an universal resistance mechanism to both first and third generation EGFR inhibitors
Authors: Shi Puyu , Oh You-Take , Zhang Guojing , Yao Weilong , Yue Ping , Kanteti Rajani , Riehm Jacob , Salgia Ravi , Owonikoko Taofeek , Ramalingam Suresh S. , Chen Mingwei , Sun Shi-Yong 
Published: July 2016

Abstract
c-Met amplification and acquisition of a second T790M mutation are key mechanisms accounting for majority of resistant cases to first generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs; i.e., erlotinib). The third generation EGFR-TKIs (e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants while sparing wild-type EGFR, represent very promising therapeutic options for NSCLC patients who have become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. We show that c-Met amplification and hyperactivation is an universal mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed elevated levels of c-Met (due to gene amplification) and p-c-Met and were cross-resistant to AZD9291 or erlotinib. Both chemical and genetic inhibition of c-Met overcame the resistance of these cell lines to AZD9291 including enhancement of apoptosis or G1 cell cycle arrest. Consistently the combination of AZD9291 and c-Met inhibition effectively inhibited the growth of both erlotinib- and AZD9291-resistant HCC827 xenografts in nude mice. Hence, we suggest that inhibition of c-Met is also an effective strategy to overcome resistance of EGFR-mutated NSCLCs with c-Met amplification or hyperactivation to AZD9291, providing the rationale for clinical development of this novel combination strategy. (SSR, TKO and SYS are Georgia Research Alliance Distinguished Cancer Scientists)
Citation Format: Puyu Shi, You-Take Oh, Guojing Zhang, Weilong Yao, Ping Yue, Rajani Kanteti, Jacob Riehm, Ravi Salgia, Taofeek Owonikoko, Suresh S. Ramalingam, Mingwei Chen, Shi-Yong Sun. c-Met hyperactivation is an universal resistance mechanism to both first and third generation EGFR inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2105.
Abstract 2128: Influence of estrogen receptor status on acquisition of doxorubicin resistance in breast cancer cells
Authors: Ponnusamy Logeswari , Mahalingaiah Prathap Kumar Salakatte , Singh Kamaleshwar P. 
Published: July 2016

Abstract
Breast cancer is the most commonly diagnosed invasive cancer in women. Doxorubicin is being the mainstay treatment for solid cancers including breast cancer. However, chemotherapy resistance, either innate or acquired, is a major limitation in breast cancer treatment. The mechanism of resistance as well as the role of estrogen receptor (ER) status in doxorubicin resistance in breast cancer is not clear. Therefore, objective of this study was to determine whether ER status influence the doxorubicin resistance, and to further identify the molecular mechanism in this process. To address this question, ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cell lines were given continuous treatment of clinically relevant concentration of doxorubicin and the pattern of resistance was monitored. Resistance was evaluated using various parameters such as cell count, cell growth and cytotoxicity by MTT assay, cell cycle analysis using flow cytometer. Expression of genes and protein related to cell cycle and cell survival, drug transport, DNA damage repair, metastasis/invasion and epigenetic regulatory complex were measured by qRT- PCR and western blot respectively. Soft agar assay and wound healing assay were performed to determine the anchorage-independent growth and migration potential of resistance cells. Results of MTT assay, and cell cycle revealed that ER-positive MCF-7 cells developed relatively earlier and high level of resistance when compared to MDA-MB-231 cells. This was further confirmed by additional features such as, cancer stem cell markers, epithelial to mesenchymal transition, and increased tumorigenicity in MCF-7 cells than in MDA-MB-231 cells during resistance development. These changes were associated with alteration in drug transporters, cell cycle genes and epigenetic regulatory proteins such as HDAC1 and DNMT1. Pretreatment with demethylating agent 5-aza-deoxycytidine and HDAC inhibitor Trichostatin A significantly resensitized resistance MCF-7 and MDA-MB-231 cells to doxorubicin in comparable to sensitive parental cells. However, this resenstitivty was higher in MCF-7 cells when compared to MDA-MB-231 cells. In summary, result of this study suggests that acquisition of doxorubicin resistance depends on status of estrogen receptor in breast cancer cell lines. Additionally, this differential resistance pattern could be due to differences in epigenetic changes in these two types of breast cancers, thus the acquired resistance could be potentially resensitized using epigenetic therapy
Citation Format: Logeswari Ponnusamy, Prathap Kumar Salakatte Mahalingaiah, Kamaleshwar P. Singh. Influence of estrogen receptor status on acquisition of doxorubicin resistance in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2128.
Abstract 2137: Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia
Authors: Cherian Joseph , Nacro Kassoum , Poh Zhi Ying , Guo Samantha , Ho Melvyn Wai Tuck , Yang Haiyan , Lim Sharon , Choong Meng Ling , Joy Joma Kanikadu , Zekui Perlyn Z. , Liu Boping , Ong Esther Hongqian , Pendharkar Vishal , Ding Lijun , Poulsen Anders , Lee May Ann , Sangthongpitag Kanda , Chuah Charles , Ong Tiong S. , Hill Jeffrey , Keller Thomas H. , Matter Alex 
Published: July 2016

Abstract
Chronic Phase Chronic Myelogenous Leukemia (CP-CML) is well treated with tyrosine kinase inhibitors (TKI) through BCR-ABL kinase modulation. However, TKI are ineffective for late-stage or blast crisis (BC) CML in which phase, granulocyte macrophage progenitors (GMPs) have acquired the ability to function as leukemic stem cells (LSCs), and are thought to act as a reservoir for TKI resistance with poor prognosis. An effective BC-CML therapy will likely have to target the BC-LSC population to ensure long-term disease control.
Recent studies have shown the importance of the MAP kinase interacting serine/threonine kinase (MNK1/2)-eukaryotic translation initiation factor 4E (eIF4E) axis in sustaining BC-LSC self-renewal. Thus, a single agent which inhibits both BCR-ABL and MNK1/2 kinase simultaneously represents a rational approach to target BC-LSCs. Such an agent should be able to distinguish between normal hematopoietic stem cells (HSC) and LSCs.
Here, we report the discovery of a potential BC-CML therapy that relies on the inhibition of MNK1/2 and BCR-ABL kinases using a dual specific MNK/ABL inhibitor. We will also report the in vitro and in vivo biological data, pharmacokinetic properties, and biochemical characteristics of such compounds. These compounds are able to prevent eIF4E phosphorylation, thus selectively inhibiting the MNK-eIF4E-dependent self-renewal function of BC-LSCs as a single agent while leaving normal HSCs unscathed.
Citation Format: Joseph Cherian, Kassoum Nacro, Zhi Ying Poh, Samantha Guo, Melvyn Wai Tuck Ho, Haiyan Yang, Sharon Lim, Meng Ling Choong, Joma Kanikadu Joy, Perlyn Z. Zekui, Boping Liu, Esther Hongqian Ong, Vishal Pendharkar, Lijun Ding, Anders Poulsen, May Ann Lee, Kanda Sangthongpitag, Charles Chuah, Tiong S. Ong, Jeffrey Hill, Thomas H. Keller, Alex Matter. Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2137.
Abstract 2146: YAP is an important pathway downstream of EGFR that is a potential target for EGFR-TKI-resistance lung adenocarcinomas
Authors: Lee Ting-Fang , Tseng Yu-Chi , Liu Ying-Pu , Kao Yu-Rung , Wu Cheng-Wen 
Published: July 2016

Abstract
Epidermal growth factor receptor (EGFR) mutations are found in lung adenocarcinomas leading to tumor cells proliferation and survival. EGFR tyrosine kinase inhibitors (TKIs) that block EGFR activity are effective therapeutics for EGFR-mutant lung adenocarcinoma patients, but TKI-resistance inevitably occurs. The YES-associated protein (YAP) transcription coactivator has been implicated as an oncogene and is amplified in human cancers and provides tumor cells strong proliferation and survival cues. This study investigated the roles of YAP in lung adenocarcinoma by exploring its regulation and functions mediated by EGFR signaling. Using lung adenocarcinoma cell lines, we detected enhanced YAP expression and activity mediated by EGFR signaling due to enhanced protein stability. The Src family protein YES was involved in EGFR-regulated YAP expression. The YAP/YES pathway was crucial for proliferation in EGFR-dependent cells. Small molecules that reduced YAP levels by mechanisms bypassing EGFR were effective in killing EGFR-dependent cells including EGFR T790M, the major cause of TKI-resistance. These observations unveiled the significance of YAP in EGFR mutant lung adenocarcinomas and identified YAP as an promising therapeutic target for EGFR-dependent lung adenocarcinoma patients, including those with EGFR T790M-caused TKI resistance.
Citation Format: Ting-Fang Lee, Yu-Chi Tseng, Ying-Pu Liu, Yu-Rung Kao, Cheng-Wen Wu. YAP is an important pathway downstream of EGFR that is a potential target for EGFR-TKI-resistance lung adenocarcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2146.