title: Cellular inhibitor of apoptosis protein 1 (cIAP1) stability contributes to YM155 resistance in human gastric cancer cells.
abstract: YM155, which blocks the expression of survivin, a member of the inhibitor of apoptosis (IAP) family, induces cell death in a variety of cancer types, including prostate, bladder, breast, leukemia, and non-small lung cancer. However, the mechanism underlying gastric cancer susceptibility and resistance to YM155 is yet to be specified. Here, we demonstrate that cIAP1 stability dictates resistance to YM155 in human gastric cancer cells. Treatment of human gastric cancer cells with YM155 differentially induced cell death dependent on the stability of cIAP1 as well as survivin. Transfection with cIAP1 expression plasmids decreased cell sensitivity to YM155, whereas knockdown of endogenous cIAP1 using RNA interference enhanced sensitivity to YM155. In addition, double knockdown of survivin and cIAP1 significantly induced cell death in the YM155-resistant cell line, MKN45. We also showed that YM155 induced autoubiquitination and proteasome-dependent degradation of cIAP1. Surprisingly, survivin affected the stability of cIAP1 through binding, contributing to cell sensitivity to YM155. Thus, our findings reveal that YM155 sensitizes human gastric cancer cells to apoptotic cell death by degrading cIAP1, and furthermore, cIAP1 in gastric cancer cells may act as a PD marker for YM155 treatment.
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Soo-A
authors: SA
authors: Jung
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Yong-Man
authors: YM
authors: Park
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Seung-Woo
authors: SW
authors: Hong
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Jai-Hee
authors: JH
authors: Moon
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Jae-Sik
authors: JS
authors: Shin
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology, the Department of Life Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors: Ha-Reum
authors: HR
authors: Lee
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Seung-Hee
authors: SH
authors: Ha
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Dae-Hee
authors: DH
authors: Lee
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Jeong Hee
authors: JH
authors: Kim
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Seung-Mi
authors: SM
authors: Kim
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Jeong Eun
authors: JE
authors: Kim
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Kyu-pyo
authors: KP
authors: Kim
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Yong Sang
authors: YS
authors: Hong
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Radiation Oncology, and.
authors: Eun Kyung
authors: EK
authors: Choi
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology.
authors: Jung Shin
authors: JS
authors: Lee
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology, Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul and inno183@amc.seoul.kr.
authors: Dong-Hoon
authors: DH
authors: Jin
authors: From the Innovative Cancer Research, Asan Institute for Life Science, Departments of Oncology, twkimmd@amc.seoul.kr.
authors: TaeWon
authors: T
authors: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D000077022:Survivin; C523798:sepantronium
keywords: Anticancer Drug; Apoptosis; Gastric Cancer; Survivin; Ubiquitylation (Ubiquitination); YM155, cIAP1
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