Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling

Fujimaki, Shun; Matsuda, Yasunobu; Wakai, Toshifumi; Sanpei, Ayumi; Kubota, Masayuki; Takamura, Masaaki; Yamagiwa, Satoshi; Yano, Masahiko; Ohkoshi, Shogo; Aoyagi, Yutaka

doi:10.1016/j.canlet.2011.12.043

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Volume 319, Issue 1 , Pages 98-108, 1 June 2012

Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling

Shun Fujimaki
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, Niigata, Japan
Yasunobu Matsuda
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, Niigata, Japan
- Corresponding author. Address: Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Niigata 951-8518, Japan. Tel.: +81 25 227 2357; fax: +81 25 227 0749.
Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Ayumi Sanpei
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Masayuki Kubota
- Division of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Masaaki Takamura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Satoshi Yamagiwa
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Masahiko Yano
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Shogo Ohkoshi
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Yutaka Aoyagi
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Received 3 November 2011; received in revised form 21 December 2011; accepted 22 December 2011. published online 03 February 2012.

Abstract

Sorafenib is a multi-kinase inhibitor applicable to hepatocellular carcinoma (HCC), but its limited therapeutic effects are a major problem to be solved. Here, we show that blockade of ataxia telangiectasia mutated (ATM) improves the antitumor effects of sorafenib. When hepatoma cell lines HepG2 and PLC/PRF/5 were treated with sorafenib plus ATM small inhibitory RNAs, ATM inhibitor KU55933 or caffeine, Akt signaling was suppressed and the cytotoxic effects were significantly potentiated. Moreover, ATM inhibition effectively suppressed the sorafenib-induced cell migration. Taken together, manipulation of ATM activity might be a useful strategy for improving sorafenib treatment of HCC.

Keywords: Hepatoma, Sorafenib, Akt, Ataxia telangiectasia mutated (ATM), Caffeine