Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells

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

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48 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)100-110
Number of pages11
JournalGastric Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1

Keywords

  • Apoptosis
  • CD44
  • Cancer stem cell
  • Chemotherapy resistance

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Cancer Research

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    Akagi, H., Higuchi, H., Sumimoto, H., Igarashi, T., Kabashima, A., Mizuguchi, H., Izumiya, M., Sakai, G., Adachi, M., Funakoshi, S., Nakamura, S., Hamamoto, Y., Kanai, T., Takaishi, H., Kawakami, Y., & Hibi, T. (2013). Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells. Gastric Cancer, 16(1), 100-110. https://doi.org/10.1007/s10120-012-0153-6