bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1335: Lack of casein kinase 1 delta induces DNA damage, inhibition of mTORC1 signaling and nucleophagy
Authors: Greer Yoshimi Endo , Gao Bo , Yang Yingzi , Rubin Jeffrey S. 
Published: May 2015

Abstract
Casein kinase 1 delta (CK1δ) is a conserved serine/threonine protein kinase that regulates diverse cellular processes including vesicle trafficking, cell cycle progression, chromosomal segregation, DNA repair, circadian rhythm, neurite outgrowth and ciliogenesis. CK1δ has been reported to phosphorylate Mdm2, the E3 ubiquitin ligase for p53, resulting in Mdm2 ubiquitination/degradation and concomitant accumulation of p53, the latter functioning as a mediator of cell cycle checkpoints and DNA repair. Mice that lack Csnk1d exhibit a perinatal lethal phenotype and typically weigh 30-50% less than their wild type littermates. The exact causes of death and small size are unknown. We hypothesized that the absence of CK1δ initiates cellular stresses that adversely affect cell survival. To examine this idea, we collected mouse embryonic fibroblasts (MEFs) from mice homozygous for a Csnk1d floxed allele, and generated MEF Csnk1d null cells by infection with adenovirus expressing Cre. Endogenous p53 protein level was significantly lower in MEF Csnk1d null cells relative to MEF Ctl cells infected with adenovirus-GFP. Substantial DNA damage also was detected in MEF Csnk1d null cells, as measured by γ-H2AX staining. Flow cytometric analysis revealed that early passage (P3) MEF Csnk1d null cells exhibited a larger sub-G0 fraction (64%) than MEF Ctl cells (34%). The sub-G0 fraction decreased sharply with increasing passage number, becoming negligible by P10. In addition to the decline in sub-G0 fraction, we observed a transient population of MEF Csnk1d null cells with multiple DAPI-stained micronuclei containing both γ-H2AX and membranes positive for the autophagosomal marker LC3 and lysosomal marker LAMP1. These features were preceded by and coincided with mTORC1 pathway inactivation, as indicated by low concentrations of phospho-Akt, phospho-mTOR and phospho-S6K, consistent with the view that mTORC1 inhibition facilitates the induction of autophagy. Subsequently, these differences between MEF Csnk1d null and MEF Ctl cells subsided. Our findings demonstrate that loss of CK1δ expression in proliferating MEF cells results in DNA damage and initially a large sub-G0 peak, followed by a wave of nucleophagy and ultimately cell survival in culture. Ongoing investigation will explore whether similar processes occur in embryonic tissues from Csnk1d null mice and contribute to their pathologic phenotype.
Citation Format: Yoshimi Endo Greer, Bo Gao, Yingzi Yang, Jeffrey S. Rubin. Lack of casein kinase 1 delta induces DNA damage, inhibition of mTORC1 signaling and nucleophagy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1335. doi:10.1158/1538-7445.AM2014-1335
Abstract 1338: Blockage of nucleocytoplasmic transport by wheat germ agglutinin (WGA) induces autophagy and cell death
Authors: Tsai Tsung-Lin , Hung Chun-Hua , Wang Hao-Chen , Shieh Dar-Bin , Su Wu-Chou , Lin Chien-Chung 
Published: May 2015

Abstract
The nuclear pore complex (NPC) is a primary conduit for cellular communication between the nucleus and cytoplasm, which is essential for cellular survival and proliferation. During carcinogenesis, many oncoproteins are activated and have to send their signals into nucleus to regulate gene expression. In response to the signals, many genes are upregulated, which results in transcription of many RNA. Because both inward of transcriptional factors and outward of RNAs require interaction of these molecules with NPC, blockage of NPC may provoke serious cellular distress. Wheat germ agglutinin (WGA), a lectin that specifically binds to N-acetyl-d-glucosamine (GlcNAc) and N-acetyl-d-neuraminic acid (NeuNAc) residues on the cell surface, was reported to disrupt the function of NPC via interaction with POM121. We found that FITC-WGA had located around the cell membrane 0.5 hour after administration to culture media and reached the paranuclear region 4 hours later. The accumulation of WGA around the nucleus subsequently induced a nucleocytoplasmic transport blockage that prevented export of tRNA and import of signaling proteins (NF-κB and Nrf2) into the nucleus. Beyond the concentration of 5 μg/ml, WGA dose- and time-dependently induced cell death in HeLa, SiHa and CaSKi cell lines. The SiHa cells had more intake of WGA than HeLa and CaSKi cells did and became more sensitive to WGA treatment compared to the other two cells. After treatment with WGA in the three cells, we observed that the expression of autophagic markers (ATG5, ATG7 and LC3) are induced in 24 hours and last to 96 hours. On the contrary, the apoptotic protein caspases 3 and downstream substrates, such as poly(ADP-ribose) polymerase (PARP) were only marginally induced. Furthermore, Transmission Electron Microscopy (TEM) imaging disclosed multi-membrane vesicles (autophagosomes and autolysosomes) inside the cytoplasm after WGA treatment, confirming that the autophagy response was fully induced. These findings suggest that blockage of NPC by WGA may induced autophagy-related cell death and targeting NPC may be warranting further development into a new anti-cancer modality.
Citation Format: Tsung-Lin Tsai, Chun-Hua Hung, Hao-Chen Wang, Dar-Bin Shieh, Wu-Chou Su, Chien-Chung Lin. Blockage of nucleocytoplasmic transport by wheat germ agglutinin (WGA) induces autophagy and cell death. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1338. doi:10.1158/1538-7445.AM2014-1338
Abstract 1339: Endoplasmic reticulum stress mediates Tanshinone I induced apoptosis in mesothelioma cells
Authors: Lee JiHyun , Kim Bonglee 
Published: May 2015

Abstract
Malignant Mesothelioma (MM) is a highly aggressive tumor caused by asbestos exposure with poor survival rate. Here, we investigated anti-cancer mechanism of Tanshinone I on mesothelioma cells. Tanshinone I exerted significant cytotoxicity in a time and dose dependent manner in mesothelioma cell lines such as MSTO-211H, H28, and H2452 cells, but not in MeT-5A cells. Also, Tanshinone I increased sub-G1 population and TUNEL positive stained cells in three mesothelioma cells. Consistently, Tanshinone I cleaved poly(ADP)-ribose polymerase (PARP) and attenuated the expression of pro-caspase9, pro-caspase3 and Bcl2 as well as the phosphorylation of JNK and PI3K in three mesothelioma cells. Furthermore, Tanshinone I exerted significant cytotoxicity in a time and dose dependent manner in mesothelioma up-regulated the expression of endoplasmic reticulum (ER) stress markers such as CHOP, GRP78, ATF4, and IRE-1 in three mesothelioma cells. The apoptotic ability of Tanshinone I to cleave PARP and activate caspase 9/3 in in three mesothelioma cells. Overall, these findings suggest that Tanshinone I exhibits anti-tumor effect in MSTO-211H, H28, and H2452 cells via up-regulation of ER stress signaling as a potent anticancer agent for the mesothelioma cells.
Citation Format: JiHyun Lee, Bonglee Kim. Endoplasmic reticulum stress mediates Tanshinone I induced apoptosis in mesothelioma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1339. doi:10.1158/1538-7445.AM2014-1339
Abstract 1340: Induction of necroptosis in ovarian cancer cells as a therapeutic strategy
Authors: McCabe Katelyn E. , Bacos Karl , Lu Dan , Delaney Joe R. , Vamos Mitchell , Cosford Nicholas D. P. , Stupack Dwayne G. 
Published: May 2015

Abstract
The standard of care for ovarian cancer patients is carboplatin and paclitaxel. While many tumors initially respond to these drugs, patients often relapse with resistant disease. One of the mechanisms implicated in this development of resistance is evasion of apoptosis. Exploiting alternative death pathways, including necroptosis, is one strategy to treat such recurrent disease. Overexpressed in many cancers, inhibitor of apoptosis proteins (IAPs) represent one family of promising targets. Treatment of cells with an IAP antagonist can activate apoptosis or, if caspases are blocked, necroptosis. Among a panel of ovarian cancer cell lines screened for sensitivity to an IAP antagonist in combination with a pan-caspase inhibitor, only one (OVCAR3) was found to be sensitive, but this sensitivity was also exhibited by serous ovarian cancer cells isolated from patients. Combination treatment induces the formation of a p62-associated necrosome (RIPK1/RIPK3/FADD/caspase-8), and death can be rescued with inhibitors of RIPK1 and MLKL, two key proteins in the necroptosis pathway. All sensitive cell lines, but no resistant lines, express RIPK3 protein, and data from knockdown and ectopic expression studies demonstrate the dependency of cell death on kinase-active RIPK3, as well as caspase-8. Studies using a TNFα neutralizing antibody suggest that the combination elicits autocrine production of TNFα, which likely, in turn, activates the extrinsic death pathway in these cells. In conclusion, these findings illustrate that necroptosis can be induced in RIPK3-expressing ovarian cancer cells and indicate that in vivo studies are warranted.
Citation Format: Katelyn E. McCabe, Karl Bacos, Dan Lu, Joe R. Delaney, Mitchell Vamos, Nicholas D. P. Cosford, Dwayne G. Stupack. Induction of necroptosis in ovarian cancer cells as a therapeutic strategy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1340. doi:10.1158/1538-7445.AM2014-1340
Abstract 1344: Downregulation of mortalin increased mitochondrial fragmentation and dysfunctions
Authors: Park So Jung , Cho Dong-Hyung 
Published: May 2015

Abstract
Mitochondria are essential organelles in the establishment of tumor characteristics such as the resistance to cell death, high proliferative capacity and adaptation to unfavorable cellular environment. Mitochondrial dynamics greatly influence the function and morphology of mitochondria. Until now various post-translational modifications for mitochondrial dynamic proteins and several regulatory proteins have explained complex mitochondrial dynamics. However, the precise mechanism that coordinates these complex processes remains unclear. To further understand the regulatory machinery of mitochondrial dynamics, we screened a mitochondrial siRNA library and identified mortalin as a potential regulatory protein. Mortalin is a heat-non-inducible member of the heat shock protein 70 family and it binds to p53 and prevents p53 from entering the nucleus. Both genetic and chemical inhibition of mortalin strongly induced mitochondrial fragmentation and increased cytotoxicity as well as mitochondrial dysfunction. In contrast, overexpression of mortalin significantly suppressed mitochondrial fragmentation and cell death. Taken together, our results suggest that down-regulation of mortalin potentiates mitochondrial fragmentation and dysfunction
Note: This abstract was not presented at the meeting.
Citation Format: So Jung Park, Dong-Hyung Cho. Downregulation of mortalin increased mitochondrial fragmentation and dysfunctions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1344. doi:10.1158/1538-7445.AM2014-1344
Abstract 1345: Role of AMP-activated protein kinase in crosstalk between apoptosis and autophagy in human colon cancer
Authors: Song Xinxin , Kim Seog-Young , Zhang Lin , Lee Yong J. 
Published: May 2015

Abstract
Unresectable colorectal liver metastases remain major unsolved issues and more effective regimens are urgently needed. During screening synergistic drug combinations for colon cancer therapy, we identified a novel multimodality treatment for colon cancer cells-chemotherapeutic agent melphalan in combination with proteasome inhibitor bortezomib and mTOR (mammalian target of rapamycin) inhibitor rapamycin. We showed in this study that melphalan triggered apoptosis, bortezomib induced both apoptosis and autophagy, rapamycin caused autophagy, and the combinatorial treatment induced synergistic apoptosis which was mediated through an increase in caspase activation. We observed that mitochondrial dysfunction induced by the combination was linked with altered cellular metabolism and induced AMP-activated protein kinase (AMPK) activation, and thus resulted in Beclin-1 phosphorylated at Ser 93/96. Interestingly, Beclin-1 phosphorylated at Ser 93/96 is sufficient to induce Beclin-1 cleavage by caspase 8 for switching off autophagy to achieve the synergistic induction of apoptosis. The multimodality treatment-induced Beclin-1 cleavage was abolished in Beclin-1 double mutant (D133A/D149A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. These observations provide a novel mechanism for AMPK induced apoptosis through interplay between autophagy and apoptosis.
Citation Format: Xinxin Song, Seog-Young Kim, Lin Zhang, Yong J. Lee. Role of AMP-activated protein kinase in crosstalk between apoptosis and autophagy in human colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1345. doi:10.1158/1538-7445.AM2014-1345
Abstract 135: Phosphorylation and furin-mediated processing are critical posttranslational modifications of the KISS1 metastasis suppressor
Authors: Harihar Sitaram , Hampton Kelsey R. , Iwakuma Tomoo , Seidah Nabil G. , Welch Danny R. 
Published: May 2015

Abstract
Originally discovered as a metastasis suppressor, KISS1 has since been defined as a neurotransmittor and regulator of diverse cellular functions and has been implicated in pathologies such as hypogonadism and Alzheimer's disease. Several laboratories are actively developing therapies based upon KISS1 biology. KISS1 is secreted and processed into small peptides (called kisspeptins (KP)) in the extracellular milieu. However, the enzyme(s) responsible for generation of KP from nascent KISS1 is unknown, although sequence analysis (cleavage at KR or RR dibasic sites) suggests that proprotein convertases (PC) are responsible. We hypothesized that enzyme(s) belonging to the PC family processes KISS1 to generate KP. KISS1 processing was completely inhibited by treatment with PC inhibitors Dec-RVKR-CMK and a1-PDX in these cells multiple tumor cell lines. Further, mRNA expression of the seven members of the PC family showed consistent expression of only three proteases - furin, PCSK5 and PCSK7 narrowing the candidate proteases. Only shRNA-mediated knockdown of furin (i.e., not PCSK5 or PCSK7) blocked KISS1 processing. Thus furin is the essential enzyme responsible for KP generation. Even when cells were exposed to Dec-RVKR-CMK or shRNA targeting furin, two bands (Mr∼15.9 kDa and Mr ∼17 kDa) were consistently detected in SDS-PAGE of conditioned medium. This observation suggested KISS1 could either be alternatively post-translationally modified or that another protease (family) might also cleave KISS1. To investigate the possibility that KISS1 may be post-translationally modified, potential sites of O-glycosylation (NetOGlyc 4.0) or serine/threonine phosphorylation (NetPhos 2.0) were analyzed in silico. Three amino acid residues (T69, S70, and S72)of the native KISS1 protein showed highest scores as being either O-glycosylated or phosphorylated. Further, mutation of these three residues to alanine resulted in the loss of the higher molecular weight band which was co-localized to a band detected using anti-phospho Ser/Thr strongly suggesting that KISS1 is indeed phosphorylated. This is the first report of phosphorylation of KISS1. Studies are underway to identify the kinase(s) and phosphatase(s) involved as well as the functional significance of the phosphorylation. Support: CA134981, National Foundation for Cancer Research, Steiner Family Fellowship in Metastasis Research, Susan G. Komen for the Cure SAC110037.
Citation Format: Sitaram Harihar, Kelsey R. Hampton, Tomoo Iwakuma, Nabil G. Seidah, Danny R. Welch. Phosphorylation and furin-mediated processing are critical posttranslational modifications of the KISS1 metastasis suppressor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 135. doi:10.1158/1538-7445.AM2014-135
Abstract 1351: Expression of klotho enhances the apoptotic response of cancer cells to anticancer agents
Authors: Kudo Yujin , Usuda Jitsuo , Furumoto Hideyuki , Maehara Sachio , Ohtani Keishi , Inoue Tatsuya , Ishizumi Taichiro , Kato Yasufumi , Kakihana Masatoshi , Kajiwara Naohiro , Ohira Tatsuo , Ikeda Norihiko 
Published: May 2015

Abstract
(Introduction)
We have reported that the klotho gene, which is an anti-aging gene known to be a tumor suppressor, is a prognostic factor for lung cancer patients. In this study, we determined whether klotho expression may have a predictive value of the efficacy of anti-cancer agents for cancer treatment.
(Methods)
We performed co-transfection of klotho and GFP-plasmid into MCF-7c3 cells, which stably express procaspase-3, and treated the cells with various kinds of anti-cancer agents. We observed typical apoptosis morphologically using fluorescent microscopy and evaluated the apoptotic response.
(Results)
Western blot analysis revealed high klotho expression in the cells transfected with the klotho gene plasmid. There was no evidence of klotho expression in the normal MCF-7c3 cells. The anti-cancer drug sensitivity test showed that docetaxel significantly induced more typical apoptosis in the cells with klotho than in the cells without klotho (41.2% and 18.3%, respectively; p &lt; 0.05). Paclitaxel also significantly induced more typical apoptosis in the cells with klotho than in the cells without klotho (34.9% and 14.9%, respectively; p &lt; 0.05). However, there was no significant difference in the apoptosis rates induced by other anti-cancer drugs, such as cisplatin, carboplatin, pemetrexed, gemicitabine, vinorelbine, etoposide, and gefitinib.
(Conclusion)
A high expression of the klotho protein can markedly increase the apoptotic response of MCF-7c3 cells to docetaxel and paclitaxel. These results suggest that klotho expression may indicate the predictive value of chemotherapy and play an important role in cancer treatment.
Apoptosis induced by taxane-induced stratified expression of klotho proteinRate of apoptosisDocetaxelPaclitaxelA: Klotho(-)/GFP(-)14.8%19.3%A vs B: p&gt;0.05A vs B: p&gt;0.05B: Klotho(-)/GFP(+)18.3%14.9%B vs C: p=0.01B vs C: p=0.03C: Klotho(+)/GFP(+)41.2%35.9%
Citation Format: Yujin Kudo, Jitsuo Usuda, Hideyuki Furumoto, Sachio Maehara, Keishi Ohtani, Tatsuya Inoue, Taichiro Ishizumi, Yasufumi Kato, Masatoshi Kakihana, Naohiro Kajiwara, Tatsuo Ohira, Norihiko Ikeda. Expression of klotho enhances the apoptotic response of cancer cells to anticancer agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1351. doi:10.1158/1538-7445.AM2014-1351
Abstract 1352: Cytoplasmic galectin-7 has an antiapoptotic function by decreasing p53 nuclear translocation in breast cancer cells
Authors: Grosset Andrée-Anne , Gagné Donald , Labrie Marilyne , Vladoiu Maria , Gaboury Louis , Doucet Nicolas , St-Pierre Yves 
Published: May 2015

Abstract
Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 was recently shown to be specifically expressed in basal-like and HER-2 positive but not in luminal subtypes of human breast cancer. Overexpression of galectin-7 in breast cancer cells also increases lung and bone metastases. However, the molecular mechanisms used by galectin-7 to increase the dissemination of breast cancer cells remain largely unknown. Although galectins are best known for their ability to bind cell surface receptors, there is increasing evidence that their intracellular forms have important functions in cancer cells. This is particularly true in the control of apoptosis. Up to now, regulation of apoptosis by intracellular galectins has been largely attributed to their ability to translocate to mitochondria, possibly following their interaction with bcl-2. Here, we report that a mutant of galectin-7 that is unable to translocate to mitochondria and nucleus induces resistance of human breast cancer cells to apoptosis induced by etoposide or by hypoxia-mimicking conditions. Surprisingly, this mutant and the wild-type form of galectin-7 bind equally well to bcl-2 in vitro and in vivo. Interestingly, both forms decreases the translocation of p53 to the nucleus and reduce the expression of p21 following treatment with doxorubicin. These results challenges the current paradigm that mitochondrial galectins are important for resistance to apoptosis and call for a greater focus on the role of cytosolic galectins in cancer cells. Our data also indicate that targeting cytosolic galectin-7 could improve the efficacy of anti-cancer drugs for the treatment of aggressive forms of breast cancer.
Citation Format: Andrée-Anne Grosset, Donald Gagné, Marilyne Labrie, Maria Vladoiu, Louis Gaboury, Nicolas Doucet, Yves St-Pierre. Cytoplasmic galectin-7 has an antiapoptotic function by decreasing p53 nuclear translocation in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1352. doi:10.1158/1538-7445.AM2014-1352