Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer.

Abstract

Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer.

• Authors: Yoku Hayakawa, Yoshihiro Hirata, Hayato Nakagawa, Kei Sakamoto, Yohko Hikiba, Hiroto Kinoshita, Wachiko Nakata, Ryota Takahashi, Keisuke Tateishi, Motohisa Tada, Masao Akanuma, Haruhiko Yoshida, Kohsuke Takeda, Hidenori Ichijo, Masao Omata, Shin Maeda, Kazuhiko Koike
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 2 Pg. 780-5 (Jan 11 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21187402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• E2F Transcription Factors
• Cyclin D1
• MAP Kinase Kinase Kinase 5
• Map3k5 protein, mouse

Topics

• Animals
• Apoptosis
• Cell Cycle
• Cell Line, Tumor
• Cyclin D1 (metabolism)
• Disease Models, Animal
• E2F Transcription Factors (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Kinase Kinase 5 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Signal Transduction
• Stomach Neoplasms (metabolism)