bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 697: Degradation of cancer mitochondria by the mitochondria-eating protein induces iron-dependent cancer cell death
Authors: Nakamura Yasuyuki , Ikari Naoki , Arakawa Hirofumi 
Published: August 2019

Abstract
Parkin/Pink1-mediated mitophagy plays a critical role in mitochondrial quality control, in which the unhealthy mitochondria are sequestered by autophagosomes, and degraded by fusion between autophagosomes and lysosomes. Here, we report non-canonical mitophagy as a new function of tumor suppressor p53. The mitochondria-eating protein (Mieap) was originally identified as a p53-target gene. Mieap induced large vacuole-like structures (Mieap-induced vacuoles: MIVs) in cancer cells. MIVs were generated from around the mitochondria, and directly ate and degraded cancer mitochondria without autophagosomes. Therefore, we defined the function as the Mieap-regulated non-canonical mitophagy. UVRAG was found to be a Mieap-interacting protein that mediates the MIVs formation. Interestingly, degradation of cancer mitochondria by the MIVs induced cell death via iron-dependent production of reactive oxygen species. Introduction of exogenous Mieap strikingly suppressed in vivo tumor growth of Mieap-deficient colorectal cancer cells. Deficiency of endogenous Mieap dramatically promoted cancer development, malignancy, and aggressiveness in colorectal and gastric cancer model mice. The Mieap-induced cell death was found to occur in in vivo hypoxic tumor microenvironment of colorectal cancer tissues. These results suggest that degradation of cancer mitochondria by Mieap-regulated non-canonical mitophagy plays a critical role in p53 tumor suppression via iron-dependent cancer cell death.
Citation Format: Yasuyuki Nakamura, Naoki Ikari, Hirofumi Arakawa. Degradation of cancer mitochondria by the mitochondria-eating protein induces iron-dependent cancer cell death [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 697.
Abstract 698: Enhancing apoptosis to improve the therapy of EGFR-mutant lung cancer
Authors: Tanaka Kosuke , Han Song , Ganesan Yogesh T. , Hsieh James J. , Cheng Emily H. 
Published: August 2019

Abstract
EGFR-TKIs have shown clinical efficacy in EGFR-mutant lung cancer patients, but most of the cases eventually develop resistance to the drugs, including the third-generation EGFR-TKI. Here, we develop a cell death mechanism-based combination strategy to enhance the therapeutic effect of EGFR-TKIs as well as to overcome the acquired resistance to EGFT-TKI in EGFR-mutant lung cancer. Through high-throughput screening of a custom pathway inhibitor library (-1000 drugs), we discovered Aurora kinase inhibitors that synergized with a third-generation EGFR-TKI (AZD9291) to induce apoptosis in EGFR-mutant lung cancer cells. Aurora kinase inhibitors enhanced AZD9291-mediated induction of BIM and PUMA, two important sentinels interconnecting the EGFR signal transduction pathway and the mitochondrial apoptotic machinery BAX and BAK. Combined inhibition of Aurora kinases and EGFR prevented the emergence of EGFR-TKI resistant clones in clonogenic assays. Interestingly, AZD9291 resistant lung cancer cells exhibited greater sensitivity to Aurora kinase inhibitors compared with parental cells. In conclusion, we found that the combination of AZD9291 and Aurora kinase inhibitors synergistically induced BIM and PUMA-mediated apoptosis, which may render a promising strategy to improve the therapy of EGFR-mutant lung cancer. &lt;!–EndFragment–&gt;
Citation Format: Kosuke Tanaka, Song Han, Yogesh T. Ganesan, James J. Hsieh, Emily H. Cheng. Enhancing apoptosis to improve the therapy of EGFR-mutant lung 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 698.
Abstract 699: KMT2A regulates cervical cancer cell growth andapoptosisthrough cooperation with VDAC1
Authors: Zhang Changlin , Li Yizhuo , Long Qian , Liu Tianze , Qin Ge , Shi Dingbo , Chen Miao , Zhang Kefang , Shi Shuihan , Deng Wuguo 
Published: August 2019

Abstract
Cervical cancer is an aggressive cutaneous malignancy, illuminating the exact mechanisms of tumorigenesis and discovering novel therapeutic targets are urgently needed. Lysine methyltransferase 2A (KMT2A) is a transcriptional co-activator regulating gene expression during early development and hematopoiesis, but the role of KMT2A in cervical cancer remains largely unknown. Here, we showed that KMT2A regulated cervical cancer cell growth and apoptosis through cooperation with VDAC1 (voltage dependent anion channel 1). Knockdown of KMT2A significantly inhibited cell viability and cell migration and induced apoptosis in cervical cancer cells. Overexpression of VADC1 reversed the KMT2A knockdown-mediated suppression of cell viability and cell migration and induction of apoptosis. The results from a xenograft mouse model confirmed that KMT2A regulated cervical cancer growth via the VDAC1 signaling. Moreover, analyses of clinical samples demonstrated that the expression of KMT2A and VDAC1 were positively correlated in cervical cancer tissues, especially in cervical intraepithelial neoplasia (CIN) samples. Collectively, our results indicated that KMT2A promoted cervical cancer growth by cooperating with the VDAC1, suggesting that the KMT2A/VDAC1 signaling pathway may be a potential therapeutic target for cervical cancer.
Citation Format: Changlin Zhang, Yizhuo Li, Qian Long, Tianze Liu, Ge Qin, Dingbo Shi, Miao Chen, Kefang Zhang, Shuihan Shi, Wuguo Deng. KMT2A regulates cervical cancer cell growth andapoptosisthrough cooperation with VDAC1 [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 699.
Abstract 7: Discovery of OICR-10268: A potent and selective BCL6 inhibitor
Authors: Watson Iain D. , Isaac Methvin , Wilson Brian , Chau Anh , Morin Justin , Subramanian Pandiaraju , Mamai Ahmed , Joseph Babu , Prakesch Michael , Uehling David , Abibi Ayome , Marcellus Richard , Strathdee Craig , Subramaniam Ratheesh , Theriault Brigitte , Winston Jeffrey , Chan Manuel , Griffin Carly , Cheung Herman , Kiyota Taira , Undzys Elijus , Aman Ahmed , Poda Gennady , Kuntz Doug , Pomroy Neil C. , Privé Gil G. , Al-awar Rima 
Published: August 2019

Abstract
The transcription factor B cell lymphoma 6 (BCL6) is required for the generation of an effective humoral immune response through the development and maintenance of germinal centers (GCs). The inhibition of the protein−protein interaction between BCL6 and its corepressors has been implicated as a therapeutic target for diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin’s lymphoma (NHL). Using structure-based drug design, we initiated a program to identify novel BCL6 inhibitors. We identified a high micromolar virtual screening hit which was then optimized for potent biophysical binding and anti-proliferative cellular activity resulting in the identification of OICR-10268, a potent and selective Bcl6 inhibitor.
Citation Format: Iain D. Watson, Methvin Isaac, Brian Wilson, Anh Chau, Justin Morin, Pandiaraju Subramanian, Ahmed Mamai, Babu Joseph, Michael Prakesch, David Uehling, Ayome Abibi, Richard Marcellus, Craig Strathdee, Ratheesh Subramaniam, Brigitte Theriault, Jeffrey Winston, Manuel Chan, Carly Griffin, Herman Cheung, Taira Kiyota, Elijus Undzys, Ahmed Aman, Gennady Poda, Doug Kuntz, Neil C. Pomroy, Gil G. Privé, Rima Al-awar. Discovery of OICR-10268: A potent and selective BCL6 inhibitor [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 7.
Abstract 70: Oxidative stress and cell death in multidrug-resistant cancer
Authors: Aryal Baikuntha P. , Gillet Jean-Pierre , Rao V Ashutosh 
Published: August 2019

Abstract
Reactive oxygen species (ROS) are constantly generated in mitochondria as a consequence of normal cellular metabolic reactions and play vital roles in cell signaling and homeostasis. Prolong production of elevated levels of ROS may lead to oxidative damage, genetic instability, and genetic mutation causing cancer initiation and progression. One proposed therapeutic strategy is to alter oxidative stress from a ROS-induced tumor promoting event to a ROS-induced apoptotic signaling to kill cancer cells. Most ROS inducing therapeutic agents initially induce ROS to kill cancer cells by apoptosis; however, prolonged exposure of such drugs may increase ROS scavenging enzymes resulting in a reduced ROS levels and an adaptive microenvironment that makes cancer cells resistant to the same ROS-inducing therapeutic agents. Chronic exposure of ROS may also upregulate the multidrug resistance associated protein expression in cancer cells. We hypothesize that induction of oxidative stress may sensitize drug resistant cancer cells leading to cell death. We used two pairs of cell lines, a mitoxantrone sensitive and mitoxantrone resistant MCF7 human breast adenocarcinoma (MCF7/MCF7MX) and a H460 non-small lung cancer cell line (H460/H460MX) for our experiments to study the impact of oxidative stress on drug resistance. We employed western blot, ELISA assays, and FACS analysis to determine the total and specific protein oxidative carbonylation, protein aggregation, and cell death by apoptosis or necrosis. At basal level, both mitoxantrone resistant MCF7MX and H460MX cells showed slightly lower level of total protein carbonylation compared to their mitoxantrone sensitive counterparts. Chemical induction of oxidative stress by external sources increased the total protein carbonylation and cell death in both mitoxantrone sensitive and resistance cancer cells. We also observed an increase in protein aggregation with increasing oxidative stress. Our results indicate that oxidative stress-induced protein oxidation by carbonylation and aggregation of oxidized protein which may sensitize drug resistant cancer cells leading to cell death.
Citation Format: Baikuntha P. Aryal, Jean-Pierre Gillet, V Ashutosh Rao. Oxidative stress and cell death in multidrug-resistant 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 70.
Abstract 705: Tumor intrinsic PD-L1 is mediated by BRAFV600E and can regulate drug-induced apoptosis in human colon cancer
Authors: Feng Daofu , Pal Krishnendu , Mukhopadhyay Debabrata , Liu Xin , Dong Haidong , Huang Shengbing , Sinicrope Frank A. 
Published: August 2019

Abstract
Resistance to chemotherapy remains a major obstacle to improving outcomes of cancer treatment. Recent data suggest intrinsic functions of immune checkpoint proteins, including PD-L1, that may be distinct from their immunoregulatory roles. We found that colorectal cancer (CRC) cells with mutant BRAF(V600E) or KRASalleles show increased PD-L1 transcripts and expression of cell surface PD-L1 protein compared to those with wild-type copies. Furthermore, ectopic expression of BRAFV600E or mutant KRAS induced PD-L1 whose upregulation was attenuated by inhibition of RAS-RAF-MEK-ERK signaling. Combined knockdown of MEK/ERK effectors c-JUN and YAP markedly reduced PD-L1. Knockout of PD-L1 in RKO cells resulted in a reduction in chemotherapy-induced DNA double strand breaks (pH2AX) and caspase-3 cleavage compared to parental cells. Results were confirmed in PD-L1 knockout MC38 murine CRC cells where re-expression of PD-L1, but not its deletion mutants, was shown to induced pH2AX and apoptosis. In cells with knockout of PD-L1, reductions in p-AKT and the BH3-only proteins BIM and BIK were observed that could be restored by re-expression of PD-L1. Treatment of cells with an anti-PD-L1 antibody reduced p-AKT, BIM and BIK, and also attenuated chemotherapy-induced apoptosis. Re-expression of BIM in PD-L1 knockout cells restored apoptosis. Murine tumor xenografts generated from cells with knockout of PD-L1 displayed resistance to oxaliplatin-induced tumor regression compared to tumors derived from parental cells. Using TCGA datasets, human CRCs with high vs low PD-L1 mRNA levels were significantly associated with better survival. In summary, we identified a non-immune function of tumor cell-intrinsic PD-L1 that upregulates BH3-only proteins BIM and BIK to promote apoptosis, thereby suggesting its potential as a predictive biomarker.
Citation Format: Daofu Feng, Krishnendu Pal, Debabrata Mukhopadhyay, Xin Liu, Haidong Dong, Shengbing Huang, Frank A. Sinicrope. Tumor intrinsic PD-L1 is mediated by BRAFV600E and can regulate drug-induced apoptosis in human colon 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 705.
Abstract 709: Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway
Authors: Jang Ik-Soon 
Published: August 2019

Abstract
The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-κB signaling is significantly activated by CCL5. However, the role of NF-κB inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-κB activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-κB signaling induced apoptosis in SKOV-3 cells via the serial activation of caspases. In addition, immune-blotting analysis showed that CCL5 is highly expressed in SKOV-3 cells. In addition to activating caspases, we show that, cordycepin prevents TNF-α-induced increase in CCL5, Akt, NF-κB, and c-FLIPLactivation and that CCL5 siRNA could inhibit Akt/NF-κB signaling. Moreover, cordycepin negatively regulated the TNF-α-mediated IκB/NF-κB pathway and c-FLIPL activation to promote JNK phosphorylation, resulting in caspase-3 activation and apoptosis. Also, we show that c-FLIPL is rapidly lost in NF-κB activation-deficient. siRNA mediated c-FLIP inhibition increased JNK. SP600125, a selective JNK inhibitor, downregulated p-JNK expression in cordycepin-treated SKOV-3 cells, leading to suppression of cordycepin-induced apoptosis. Thus, these results indicate that cordycepin inhibits CCL5-mediated Akt/NF-κB signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Ik-Soon Jang. Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway [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 709.
Abstract 710: Real-time apoptosis and necrosis detection in 3D spheroid cellmodels
Authors: Niles Andrew L. , Kupcho Kevin R. , Riss Terry L. , Lazar Dan F. , Cali James J. 
Published: August 2019

Abstract
The structural and biological complexity of cancer spheroids make them uniquely suited to address or approximate the pharmacodynamics of new chemical entities directed at chemotherapeutic reduction of tumor masses. Unfortunately, this same complexity represents a substantial technical challenge for measuring apoptosis and necrosis using conventional methods in real time. To address this challenge, we explored the use of a multiplexed bioluminescent and fluorescent, real-time assay reagent which utilizes annexin V fusion proteins containing binary elements of a complementing luciferase, a time-released luciferase substrate and an excludable DNA membrane integrity dye. The assay reagent was added to HCT-116 and HepG2 spheroids dosed with serial dilutions of panobinostat, bortezomib, or paclitaxel to examine the magnitude, potency and kinetics of the responses. Luminescent and fluorescent data were continuously collected throughout the 48h exposure using a conventional multimode plate reader equipped with atmospheric control. After the exposure period, the treated spheroids were imaged by fluorescence microscopy to assess necrotic burden as well as analyzed for remaining cellular viability using ATP content compared to untreated control. Consistent with their known modes of cytotoxic action, bortezomib produced the first measurable phoshatidylserine (PS) exposure (~8h), followed by panobinostat (~12h) and paclitaxel (18-22h). The apoptotic potencies and magnitudes of response matured thereafter as a function of time until 48h. Secondary necrosis resulting from completion of the apoptotic program lagged PS exposure in both time and magnitude. Imaging results for necrosis and ATP determinations provided orthogonal and inversely complementary verification of data values obtained with the apoptosis assay reagent. Taken together, this workflow may help define the in vitro pharmacological disposition of new chemical entities with respect to their capability to penetrate and induce apoptosis in spheroids and/or other more complex multicellular models.
Citation Format: Andrew L. Niles, Kevin R. Kupcho, Terry L. Riss, Dan F. Lazar, James J. Cali. Real-time apoptosis and necrosis detection in 3D spheroid cellmodels [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 710.
Abstract 714: Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells
Authors: Yun Hye Kyeong , Jeong Soyeon , Jeong Yoon A , Jo Min Jee , Kim Jung lim , Park Seong Hye , Kim Bo Ram , Na Yoo Jin , Kim Dae Young , Kim Bu Gyeom , Lee Dae Hee , Oh Sang Cheul 
Published: August 2019

Abstract
Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known. The authors aimed to evaluate the apoptotic action of CBD in colorectal cancer cells (CRC), and focused on its effects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway. CBD experiments were performed using the colorectal cancer cell lines HCT116 and DLD-1. CBD induced an apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed a significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, authors downregulated Noxa levels using siRNA and confirmed that the expression of apoptosis markers was decreased. After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa. The Noxa and ROS are well-known pro-apoptotic signaling agents. As a result, CBD was found to induce apoptosis in a Noxa-and-ROS-dependent manner. The effects of CBD treatment were re-demonstrated in vivo, thus confirming its role as a novel, reliable anticancer drug
Citation Format: Hye Kyeong Yun, Soyeon Jeong, Yoon A Jeong, Min Jee Jo, Jung lim Kim, Seong Hye Park, Bo Ram Kim, Yoo Jin Na, Dae Young Kim, Bu Gyeom Kim, Dae Hee Lee, Sang Cheul Oh. Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal 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 714.
Abstract 716: Chakasaponin I from tea (Camellia sinensis) flower induce anti-proliferative effect and apoptosis of cisplatin-resistant ovarian cancer cells
Authors: Chen Yi C. 
Published: August 2019

Abstract
Ovarian cancer has the highest rate of death among gynecological malignancy and ranks fifth in cancer deaths among women. Adverse side effects and acquired resistance to conventional chemotherapy based on platinum drive the exploration of other anticancer therapies,thus natural products have drawn greater attention for cancer treatment in recent years. Tea (Camellia sinensis) flower being an abundant agricultural by-product in China and Japan, has been studied for its bio-functional effects. A recent research showed that tea flower saponins (TFS) could induce anti-proliferative effect and cell cycle arrest in human ovarian cancer cells. In the present study, Chakasaponin I, one of the major constituents in TFS, whose main structure is oleanane-type triterpene, showed strong growth inhibitory effects on cisplatin-resistant OVCAR-3 cells at 3 μM by MTS assay. Such inhibitory effects might result from the induction of apoptosis. Western blot assay, Hoechst 33342 staining assay, and flow cytometry analysis were used to examine the effects of Chakasaponin I on apoptosis. The results showed that Chakasaponin I treatment dose-dependently activated the pro-apoptotic proteins (Bad and Bax) and therefore induced apoptosis might by the intrinsic apoptotic pathway.
Citation Format: Yi C. Chen. Chakasaponin I from tea (Camellia sinensis) flower induce anti-proliferative effect and apoptosis of cisplatin-resistant ovarian 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 716.
Abstract 719: Combination of atypical protein kinase-C inhibitor and 5-fluorouracil retards the proliferation of colorectal cancer cells
Authors: Islam S M Anisul , Dey Avijit , Acevedo-Duncan Mildred 
Published: August 2019

Abstract
Colorectal cancer (CRC) is the third most common malignancy and considered as the fourth most common cause of cancer-related death worldwide. Although the number of CRC survivors with stage II and III are increasing, more than 50% of patients are diagnosed with stage III or beyond where the distant disease progression has already occurred. Surgical removal of cancerous tissue coupled with chemotherapeutic intervention is the main treatment of metastatic CRC and only hope of enhanced survival. The treatment of metastatic CRC considered palliative for many years aiming for an improved life, with little hope of a cure, highlighting the need for developing novel targeted therapy for CRC. Dysregulation of kinases has been shown to be pivotal of the various pathological process including cancer. Human protein kinases constitute a complicated system with intricate internal and external interaction which stimulates various cellular processes such as cell growth, metabolism, survival, and apoptosis. In this study, a combination of atypical protein kinase c (aPKC) inhibitor (ICA-I, PKC-ι inhibitor or ζ-Stat, PKC-ζ inhibitor) and 5-FU was used to examine the effect of aPKC and thymidylate synthase on CRC cells viability. The cell lines tested were LoVo and RKO CRC cells. Our findings showed that the combination of aPKC inhibitor and 5-FU significantly reduced the viability and induce apoptosis of CRC cells. These data suggest that the simultaneous knockdown of upstream aPKC protein and downstream DNA replication would be a useful approach to combat CRC and to improve overall patients’ survival rate. These results indicate the possibility of utilizing aPKC as the potential therapeutic targets in addition to blocking DNA synthesis in metastatic CRC.
Citation Format: S M Anisul Islam, Avijit Dey, Mildred Acevedo-Duncan. Combination of atypical protein kinase-C inhibitor and 5-fluorouracil retards the proliferation of colorectal 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 719.