PMID- 21601561 OWN - NLM STAT- MEDLINE DCOM- 20110916 LR - 20211203 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 82 IP - 3 DP - 2011 Aug 1 TI - Sorafenib induces apoptotic cell death in human non-small cell lung cancer cells by down-regulating mammalian target of rapamycin (mTOR)-dependent survivin expression. PG - 216-26 LID - 10.1016/j.bcp.2011.04.011 [doi] AB - Sorafenib, a multikinase inhibitor, is emerging as a promising targeted agent that may possess antitumor activity against a broad range of cancers. The mechanism by which sorafenib induces lung cancer cell death and apoptosis, however, is not understood. In the present study, we provide evidence that sorafenib acts through inhibition of mammalian target of rapamycin (mTOR) to down-regulate survivin and promote apoptotic cell death in human non-small cell lung cancer (NSCLC) cells. Sorafenib induced ATF4-mediated Redd1 expression, leading to mTOR inhibition-the upstream signal for down-regulation of survivin. Overexpression of survivin reduced sorafenib-induced apoptosis, whereas silencing survivin using small interfering RNA (siRNA) enhanced it, supporting the interpretation that down-regulation of survivin is involved in sorafenib-induced cell death in human NSCLC cells. Furthermore, sorafenib abolished the induction of survivin that normally accompanies IGF-1-stimulated mTOR activation. We further found that Redd1-induced mTOR down-regulation and ATF4/CHOP-induced expression of the TRAIL receptor DR5 associated with sorafenib treatment helped sensitize cells to TRAIL-induced apoptosis. Our study suggests that sorafenib mediates apoptotic cell death in human NSCLC cells through Redd1-induced inhibition of mTOR and subsequent down-regulation of survivin, events that are associated with sensitization to TRAIL-induced apoptotic cell death. CI - Copyright (c) 2011 Elsevier Inc. All rights reserved. FAU - Kim, Young-Sun AU - Kim YS AD - Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea. FAU - Jin, Hyeon-Ok AU - Jin HO FAU - Seo, Sung-Keum AU - Seo SK FAU - Woo, Sang Hyeok AU - Woo SH FAU - Choe, Tae-Boo AU - Choe TB FAU - An, Sungkwan AU - An S FAU - Hong, Seok-Il AU - Hong SI FAU - Lee, Su-Jae AU - Lee SJ FAU - Lee, Kee-Ho AU - Lee KH FAU - Park, In-Chul AU - Park IC LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20110513 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Antineoplastic Agents) RN - 0 (BIRC5 protein, human) RN - 0 (Benzenesulfonates) RN - 0 (Inhibitor of Apoptosis Proteins) RN - 0 (Phenylurea Compounds) RN - 0 (Pyridines) RN - 0 (Survivin) RN - 25X51I8RD4 (Niacinamide) RN - 9ZOQ3TZI87 (Sorafenib) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Antineoplastic Agents/*pharmacology MH - Apoptosis/*drug effects MH - Benzenesulfonates/*pharmacology MH - Carcinoma, Non-Small-Cell Lung/drug therapy/pathology MH - Cell Line, Tumor MH - Down-Regulation/*drug effects MH - Gene Expression Regulation, Neoplastic/physiology MH - Humans MH - Inhibitor of Apoptosis Proteins/genetics/*metabolism MH - Lung Neoplasms/drug therapy/pathology MH - Niacinamide/analogs & derivatives MH - Phenylurea Compounds MH - Pyridines/*pharmacology MH - Sorafenib MH - Survivin MH - TOR Serine-Threonine Kinases/genetics/*metabolism EDAT- 2011/05/24 06:00 MHDA- 2011/09/17 06:00 CRDT- 2011/05/24 06:00 PHST- 2011/01/14 00:00 [received] PHST- 2011/04/20 00:00 [revised] PHST- 2011/04/22 00:00 [accepted] PHST- 2011/05/24 06:00 [entrez] PHST- 2011/05/24 06:00 [pubmed] PHST- 2011/09/17 06:00 [medline] AID - S0006-2952(11)00284-X [pii] AID - 10.1016/j.bcp.2011.04.011 [doi] PST - ppublish SO - Biochem Pharmacol. 2011 Aug 1;82(3):216-26. doi: 10.1016/j.bcp.2011.04.011. Epub 2011 May 13.