bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1653: Regulation of autophagy and apoptosis by a natural triterpenoid in diffuse large B-cell lymphoma.
Authors: Doonan Bently , Hossain Azim , Radwan Faisal , Haque Azizul 
Published: August 2014

Abstract
Diffuse large B-cell lymphoma (DLBCL), a subtype of non-Hodgkin's lymphoma, is the most common lymphoid malignancy in the western world. Treatment of DLBCL has been greatly improved in recent years with the addition of the monoclonal antibody Rituximab to the gold standard
CHOP chemotherapy regimen, but these treatments are often ineffective in patients with highly aggressive disease or in patients of advanced age. A real problem given the population of DLBCL patients is largely 60 years of age or older, these chemotherapeutics also present the issue of severe toxicity to the patient(s). Thus, studies have focused lately on natural products that can selectively kill malignant lymphomas while displaying a reduced host toxicity profile. Here, we report that a natural extract from the Ganoderma lucidum mushroom, GA-DM, induces apoptosis in human DLBCL cell lines and primary tumors, and activates an orchestrated autophagy/apoptosis pathway in the murine B-cell lymphoma cell line A20. Antitumor efficacy of
GA-DM was also investigated in vivo in a murine B-cell lymphoma model using the
A20 cell line, where GA-DM (50mg/kg) treatment reduced both the number of tumor metastases and the overall tumor burden in diseased mice. These findings support the potential use of GA-DM as a novel chemotherapeutic in the treatment of DLBCL and could improve the treatment of higher risk patients with advanced disease who can't tolerate current chemotherapy treatment.
Citation Format: Bently Doonan, Azim Hossain, Faisal Radwan, Azizul Haque. Regulation of autophagy and apoptosis by a natural triterpenoid in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1653. doi:10.1158/1538-7445.AM2013-1653
Abstract 1654: Cisplatin resistance is associated with autophagy in SPARC expressing medulloblastoma cells.
Authors: Pannuru Padmavathi , Dontula Ranadheer , Engelhard Herbert , Ozer Howard , Lakka Sajani S. 
Published: August 2014

Abstract
Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. Our previous studies indicate that SPARC expression suppressed medulloblastoma tumor growth in vitro and in vivo. We were interested in gaining further insight into the potential of SPARC expression as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. In this study, we demonstrate that SPARC: expression resulted in enhanced resistance of cancer cells to cisplatin, a commonly used chemotherapeutic drug in the treatment of medulloblastoma. We also demonstrate that autophagy was involved in SPARC expression mediated resistance to cisplatin. We further demonstrated that suppression of autophagy by autophagy inhibitors, 3-methyladenosine (3MA) and small interfering RNAs (siRNAs) targeting Atg5 in SPARC expressed cells enhanced the sensitivity of medulloblastoma cells to cisplatin compared to cells treated with cisplatin alone. Moreover, sensitization to cisplatin by inhibition of autophagy is SPARC expressed cells was accompanied by induction of apoptosis indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Further we show overexpression of High mobility group box 1 (HMGB1 in SPARC expressed cells rendered medulloblastoma cells resistant to cell death; whereas depletion of HMGB1 using RNA interference suppressed autophagy and increased the sensitivity of medulloblastoma cells to cisplatin as assessed by microtubule-associated protein 1 light chain 3 (LC3) lipidation, redistribution of LC3 into cytoplasmic puncta, and accumulation of autophagosomes and autolysosomes. Further our data suggest a role for HMGB1 in the regulation of autophagy through the MEK-ERK pathway in SPARC over expressed cells. The results of our study revealed a new mechanism for enhancing cisplatin sensitivity in SPARC expressed cells. These findings have important clinical implications for the design of experimental treatment protocols for medulloblastoma.
Citation Format: Padmavathi Pannuru, Ranadheer Dontula, Herbert Engelhard, Howard Ozer, Sajani S. Lakka. Cisplatin resistance is associated with autophagy in SPARC expressing medulloblastoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1654. doi:10.1158/1538-7445.AM2013-1654
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1657: Targeting Cullin-RING ligases by MLN4924 induces autophagy via modulating the HIF1-REDD1-TSC1-mTORC1-DEPTOR axis in breast cancer cells.
Authors: Zhao Yongchao , Xiong Xiufang , Jia Lijun , Sun Yi 
Published: August 2014

Abstract
MLN4924, a newly discovered small molecule inhibitor of NEDD8-Activating Enzyme (NAE), inactivates Cullin-RING E3 ubiquitin ligases (CRLs) by blocking cullin neddylation. As a result, MLN4924 causes accumulation of several key substrates of CRLs and effectively suppresses tumor cell growth by inducing apoptosis and senescence. However, the role of MLN4924 in induction of autophagy and its biological significance are totally unknown. Here we showed that MLN4924 effectively induces autophagy in both time- and dose-dependent manners in breast cancer cells. Mechanistically, by inactivating CRLs, MLN4924 causes accumulation of DEPTOR and HIF1α. The siRNA knockdown and gene KO studies showed that DEPTOR and the HIF1α-REDD1-TSC1 axis are responsible for MLN4924-induced autophagy via inhibiting mTORC1. Biologically, autophagy is a survival signal to tumor cells, and blockage of autophagy via siRNA knockdown, gene KO and small molecule inhibitor remarkably enhanced MLN4924-induced apoptosis. Our study reveals an uncharacterized mechanism of MLN4924 action and provides the proof-of-concept evidence for strategic drug combination of MLN4924 with an autophagy inhibitor for maximal killing of tumor cells via enhancing apoptosis.
Citation Format: Yongchao Zhao, Xiufang Xiong, Lijun Jia, Yi Sun. Targeting Cullin-RING ligases by MLN4924 induces autophagy via modulating the HIF1-REDD1-TSC1-mTORC1-DEPTOR axis in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1657. doi:10.1158/1538-7445.AM2013-1657
Abstract 1661: Autophagy induced by cathepsin S inhibition causes early ROS production for oxidative DNA damage and subsequent cell death.
Authors: Huang Chien-Chang , Chang Jang-Yang 
Published: August 2014

Abstract
Cathepsin S plays multiple roles in MHC class II antigen presentation, extracellular matrix degradation, angiogenesis, and tumorogenesis. Pharmacological inhibition of cathepsin S activity not only inhibits tumor invasion and angiogenesis but also reduces cell viability. Herein, we investigate the molecular executioner which responsible for targeting cathepsin S-induced cell death and its association with autophagy. Surprisingly, distinct from the classical regulation of autophagy by ROS, autophagy, rather than mitochondrial process, is the genuine regulator of early ROS production which responsible for consequent oxidative DNA damage and cell death. Molecular silencing of autophagy-dependent ATG genes and pharmacologic inhibition of autophagy with 3-MA and wortmannin significantly reduced ROS production, oxidative DNA damage, and cell death. Collectively, this study reveals a non-canonical molecular pathway where after the inhibition of cathepsin S, autophagy up-regulates ROS production for oxidative DNA damage and subsequently contributes to autophagy-dependent cell death. (This work was supported by the following grants: Department of Health, Taiwan DOH99-TD-C-111-004, National Health Research Institutes CA-101-PP-22, and National Research Program for Biopharmaceuticals 100CAP015-5)
Citation Format: Chien-Chang Huang, Jang-Yang Chang. Autophagy induced by cathepsin S inhibition causes early ROS production for oxidative DNA damage and subsequent cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1661. doi:10.1158/1538-7445.AM2013-1661
Abstract 1668: Induction of Autophagy by a novel agent promotes the growth arrest in breast cancer cells.
Authors: Subramani Reddy Ramadevi , Pahari Pallab , Damodaran Chendil 
Published: August 2014

Abstract
Breast cancer is a highly complex disease due to its heterogeneity in nature; that often impedes the current therapeutic options. Autophagy is a catabolic process which plays a vital role in both progressions as well as in the treatment of cancer. In fact, the role of autophagy in cancer is still unclear. Our lab is focusing on small molecules, which may induce autophagy that may result in growth arrest in breast cancer cells. In our preliminary screening studies, we have identified a small molecule, Nimocinol Acetate (NA) which induces autophagy that resulted in inhibition of growth of estrogen-positive (MCF-7) and estrogen-negative (MDA-MB-231) breast cancer cells. Molecular analysis showed the significant induction of LC-3B and ATG-3 in NA treated cells as compared to other autophagy-regulators like Atg5, Atg7, Atg12, and beclin-1, which convey the importance of ATG3 and LC3B markers in induction of autophagy. The immunofluorescence analysis confirmed the formation of acidic autophagic vesicles upon NA treatment. To further ascertain the involvement of lysosomes and autophagosomes, we specifically blocked ATG-3 and LC-3B expression by siRNA and then subjected to immunofluorescence assay. The observed results confirmed the contribution and activation of these two molecules is required for the induction of autophagy. Interestingly, no significant changes were obseverved either in the cell cycle regulation or in induction of apoptosis, which revealed that the activation of autophagy may be responsible for NA mediated growth inhibition in breast cancer cells. Currently, we are planning to conduct xenograft studies, which may suggest the in vivo efficacy and pharmacokinetic potential of NA. The present study concludes that NA could be a potential agent either alone or in combination with other chemotherapeutic agents with a novel strategy to combat breast cancer.
Citation Format: Ramadevi Subramani Reddy, Pallab Pahari, Chendil Damodaran. Induction of Autophagy by a novel agent promotes the growth arrest in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1668. doi:10.1158/1538-7445.AM2013-1668
Abstract 1669: DIRAS family members inhibit cell growth and proliferation while inducing autophagy in human ovarian cancer cells.
Authors: Sutton Margie N. , Lu Zhen , Bast Robert C. 
Published: August 2014

Abstract
Among the three members of the DIRAS family, DIRAS3 (also known as AplasiaRasHomolog Member I; ARHI) has been best characterized. ARHI is a maternally expressed imprinted tumor suppressor gene that encodes a 26 kDa GTPase with 60% homology to Ras and Rap. ARHI is downregulated in many tumor types including ovarian cancer where its re-expression at physiologic levels inhibits cancer cell growth, reduces motility, induces autophagy and promotes tumor dormancy. ARHI induces autophagy by multiple mechanism including:1) blocking PI3K-Akt signaling and inhibiting mTOR activity, 2) displacing Bcl-2 from Beclin and participating directly in the autophagy initiation complex; and 3) inducing expression of Atg4 and participating directly in the formation of autophagic vesicles, co-localizing with MAP-LC3-II in the vesicle membrane. In human cells, knockdown experiments have demonstrated that ARHI is essential for the induction of autophagy. During evolution, murine cells have lost the ARHI (DIRAS3) gene, yet can still undergo autophagy. Mice and humans express two closely related Ras-related GTPases,DIRAS1 and DIRAS2. These 22 kDa GTPases, have 30-40% overall homology with H-Ras, and 50-60% homology with ARHI (DIRAS3) with the only major difference being the truncation of the N-terminal extension. In this study, we show that transfection of DIRAS1, 2 or 3 with a selectable marker inhibits clonogenic growth of SKOv3 human ovarian cancer cells. Whereas DIRAS3 produced complete inhibition, DIRAS 1 produced 50% inhibition and D IRAS2 35% inhibition of clonogenic growth. One possible mechanism for the growth inhibition observed could be attributed to the induction of autophagy which has been shown by the formation of LC3 punctae in SKOV3 cells and the increased conversion of LC3-I to LC3-II by western blot analysis when DIRAS1 and DIRAS2 were overexpressed by transfection. These findings suggest that these DIRAS family homologs may have similar functions in limiting human tumor progression and in inducing autophagy. Future studies will examine whether DIRAS1 and DIRAS2 serve as surrogates forARHI (DIRAS3) in murine cells.
Citation Format: Margie N. Sutton, Zhen Lu, Robert C. Bast. DIRAS family members inhibit cell growth and proliferation while inducing autophagy in human ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1669. doi:10.1158/1538-7445.AM2013-1669
Abstract 1676: Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death.
Authors: Hodge James W. , Garnett Charlie T. , Farsaci Benedetto , Palena Claudia , Tsang Kwong-Yok , Ferrone Soldano , Gameiro Sofia R. 
Published: August 2014

Abstract
Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from immunogenic cell death. Docetaxel treatment of tumor cells did not induce ATP or HMGB1 secretion, or cell death. However, calreticulin exposure was observed in all cell lines examined after chemotherapy treatment. Killing by CEA, MUC-1, or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by calreticulin membrane translocation, as determined by functional knockdown of calreticulin, PERK, or calreticulin-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+, CD133+) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of “immunogenic modulation,” where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to immunogenic cell death and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy.
Citation Format: James W. Hodge, Charlie T. Garnett, Benedetto Farsaci, Claudia Palena, Kwong-Yok Tsang, Soldano Ferrone, Sofia R. Gameiro. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1676. doi:10.1158/1538-7445.AM2013-1676
Abstract 1685: Inactivation of a transcriptional variant of MAP1LC3A gene in human cancers.
Authors: Inoue Jun , Bai Hua , Kawano Tatsuyuki , Inazawa Johji 
Published: August 2014

Abstract
Autophagy functions to clear damaged or unfolded cellular components in the lysosomes as a survival pathway used by established cancers to sustain metabolism and tolerate stress. Autophagy, however, also suppress cancer initiation in liver and the accumulation of p62/SQSTM1 protein, a substrate for autophagic degradation, contributes to its tumorigenesis, suggesting that autophagy-related gene(s) may be actually inactivated in a part of human cancers at least. Recently, we have identified that a transcriptional variant of microtubule-associated protein 1 light chain 3A (LC3Av1), a member of human LC3 gene family, was frequently inactivated by aberrant DNA methylation in human cancers. Induction of wild-type LC3Av1 led to the decrease of p62 protein level, resulting in the inhibition of tumor growth, but not its mutant with the C-terminal glycine (lipidation site) changed to alanine. Thus, these results suggest that the impairment of autophagy through LC3Av1-silencing due to DNA methylation may be associated with tumorigenesis in various types of human cancer.
Citation Format: Jun Inoue, Hua Bai, Tatsuyuki Kawano, Johji Inazawa. Inactivation of a transcriptional variant of MAP1LC3A gene in human cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1685. doi:10.1158/1538-7445.AM2013-1685
Abstract 1687: Frequent inactivation of the Mieap-regulated mitochondrial quality control in colorectal cancer.
Authors: Kamino Hiroki , Nakamura Yasuyuki , Kitamura Noriaki , Futamura Manabu , Yoshida Masaki , Murai Ryuya , Saito Yuri , Sano Hitoya , Kanai Yae , Moriya Yoshihiro , Arakawa Hirofumi 
Published: August 2014

Abstract
Recently, we discovered a novel mechanism for mitochondrial quality control (MQC), in which Mieap, a p53-inducible protein, controls MQC by repairing or eliminating unhealthy mitochondria in a process known as MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), respectively (1, 2). We also reported that two mitochondrial outer membrane proteins, BNIP3 and NIX, are essential mediators of the MALM (2, 3). To examine the role of Mieap-regulated MQC pathway in tumorigenesis, we analyzed the status of p53, Mieap, BNIP3, and NIX in 57 cases of primary colorectal cancer. Of the 57 patients, Mieap and BNIP3 promoter methylation was observed in 5 (8.8%) and 26 (45.6%) patients, respectively. A p53 mutation was detected in 4 (18%) of the 22 patients with either Mieap or BNIP3 promoter methylation whereas it was found in 9 (52%) of the 17 patients with neither Mieap nor BNIP3 promoter methylation, implying that the p53/Mieap/BNIP3 pathway in the Mieap-regulated MQC is inactivated in at least 80% of colorectal cancer cases. Hypoxia induced MALM in the colorectal cancer cell line LS174T (wild-type p53, Mieap-positive, BNIP3-positive). In vitro knockdown of p53, Mieap, or BNIP3 in the LS174T cells severely inhibited hypoxia-induced MALM, leading to the accumulation of unhealthy mitochondria and increased mitochondrial reactive oxygen species (mtROS) generation. Furthermore, the mtROS dramatically enhanced cancer migration and invasion under hypoxic conditions. These results suggest that the Mieap-regulated MQC function plays a critical role in tumor suppression in colorectal cancer.
1. Miyamoto Y et al. PLoS ONE 6: e16054, 2011
2. Kitamura N et al. PLoS ONE 6: e16060, 2011
3. Nakamura Y et al. PLoS ONE 7: e30767, 2012
Citation Format: Hiroki Kamino, Yasuyuki Nakamura, Noriaki Kitamura, Manabu Futamura, Masaki Yoshida, Ryuya Murai, Yuri Saito, Hitoya Sano, Yae Kanai, Yoshihiro Moriya, Hirofumi Arakawa. Frequent inactivation of the Mieap-regulated mitochondrial quality control in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1687. doi:10.1158/1538-7445.AM2013-1687
Abstract 1692: SR16388 impairs protein homeostasis and induces autophagy in diverse human cancer cell lines.
Authors: Sambucetti Lidia C. , Zhou Wei , Calaoagan Joy , Kara Laurie , Liu Xiaohe , Sato Barbara , Samuelson Steve , Collins Nathan , Laderoute Keith 
Published: August 2014

Abstract
SR16388 is a novel amino steroid that targets estrogen-binding proteins including genomic estrogen receptors (ERs). Preclinical studies have demonstrated that SR16388 is a well-tolerated, orally active compound with compelling properties as an experimental antitumor agent: SR16388 has been demonstrated to 1) inhibit the proliferation and viability of diverse human cancer cell lines in vitro; 2) have antiangiogenic activity in vivo; and 3) reduce the growth of human tumor xenografts in mice. SR16388, which binds to and potently inhibits ERα and ERβ in breast cancer cells, also inhibits the widely expressed orphan nuclear receptor ERRα that has been implicated in the development of various human malignancies. ERRα is thought to regulate tumor cell energy metabolism associated with energy stress within solid tumor microenvironments.
We have been exploring potential mechanisms that could explain SR16388’s broad anti-proliferative effects toward human tumor cell lines with different genotypes and tissues of origin. In these studies, we observed that SR16388 can initiate a cell-cycle arrest at G1 or G2 and ultimately cause cytotoxicity (e.g., by apoptosis) even in cells that do not express ERs or ERRα. We recently observed that SR16388 can induce persistent macroautophagy (autophagy) in diverse tumor cells, including cells from hematopoietic malignancies (e.g., multiple myeloma/MM cells) in addition to carcinomas such as prostate and breast cancers. We demonstrated induction of autophagy by using established assays (e.g., LC3I/II processing; fluorescent reporters for acidic vacuole formation; long-lived protein degradation). Here we present results demonstrating that SR16388 can rapidly and potently induce autophagy in cultures of MM cells (U266, RPMI-8226) and PC3 prostate cancer cells. Induction of autophagy in PC3 cells, in particular, was detected in tumor xenografts as early as 3 hours after dosing of mice with a therapeutic dose level of SR16388. We will present data supporting the hypothesis that SR16388 exerts its anti-proliferative and anti-tumor effects in part through the induction of stress pathways modulated by perturbations of protein homeostasis. These effects could yield therapeutic benefits that derive from targets within solid tumor microenvironments.
Citation Format: Lidia C. Sambucetti, Wei Zhou, Joy Calaoagan, Laurie Kara, Xiaohe Liu, Barbara Sato, Steve Samuelson, Nathan Collins, Keith Laderoute. SR16388 impairs protein homeostasis and induces autophagy in diverse human cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1692. doi:10.1158/1538-7445.AM2013-1692