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Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells.
MedLine Citation:
PMID:  22527182     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer. METHODS: Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry. RESULTS: Six out of the 7 gastric cancer cell lines overexpressed Mcl-1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44-positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44-positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations. CONCLUSION: These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells.
Authors:
Hideko Akagi; Hajime Higuchi; Hidetoshi Sumimoto; Toru Igarashi; Ayano Kabashima; Hiroyuki Mizuguchi; Motoko Izumiya; Gen Sakai; Masayuki Adachi; Shinsuke Funakoshi; Shoko Nakamura; Yasuo Hamamoto; Takanori Kanai; Hiromasa Takaishi; Yutaka Kawakami; Toshifumi Hibi
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-24
Journal Detail:
Title:  Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association     Volume:  -     ISSN:  1436-3291     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100886238     Medline TA:  Gastric Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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