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

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

doi:10.1016/j.canlet.2011.12.043

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

Cancer Lett. 2012 Jun 1;319(1):98-108. doi: 10.1016/j.canlet.2011.12.043. Epub 2012 Jan 17.

Authors

Shun Fujimaki¹, Yasunobu Matsuda, Toshifumi Wakai, Ayumi Sanpei, Masayuki Kubota, Masaaki Takamura, Satoshi Yamagiwa, Masahiko Yano, Shogo Ohkoshi, Yutaka Aoyagi

Affiliation

¹ Department of Medical Technology, Niigata University Graduate School of Health Sciences, Niigata, Japan.

PMID: 22265862
DOI: 10.1016/j.canlet.2011.12.043

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / therapeutic use*
Ataxia Telangiectasia Mutated Proteins
Benzenesulfonates / therapeutic use*
Caffeine
Carcinoma, Hepatocellular / drug therapy*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Line, Tumor
DNA-Binding Proteins / antagonists & inhibitors*
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Liver Neoplasms / drug therapy*
Niacinamide / analogs & derivatives
Phenylurea Compounds
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Pyridines / therapeutic use*
RNA, Small Interfering
Signal Transduction / drug effects
Sorafenib
Tumor Suppressor Proteins / antagonists & inhibitors*

Substances

Antineoplastic Agents
Benzenesulfonates
Cell Cycle Proteins
DNA-Binding Proteins
Phenylurea Compounds
Pyridines
RNA, Small Interfering
Tumor Suppressor Proteins
Niacinamide
Caffeine
Sorafenib
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt