Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis

DOI PDF PubMed 被引用文献4件 参考文献36件
  • Hayato Hikita
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Takahiro Kodama
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Satoshi Tanaka
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Yoshinobu Saito
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Yasutoshi Nozaki
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Tasuku Nakabori
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Satoshi Shimizu
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Yoshito Hayashi
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Wei Li
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Minoru Shigekawa
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Ryotaro Sakamori
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Takuya Miyagi
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Naoki Hiramatsu
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Tomohide Tatsumi
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Tetsuo Takehara
    Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.

書誌事項

公開日
2015-08-01
資源種別
journal article
DOI
  • 10.1158/1940-6207.capr-15-0022-t
公開者
American Association for Cancer Research (AACR)

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説明

<jats:title>Abstract</jats:title> <jats:p>Chronic hepatitis, including viral hepatitis and steatihepatitis, is a well-known high-risk condition for hepatocellular carcinoma. We previously reported that continuous hepatocyte apoptosis drives liver tumors in hepatocyte-specific Bcl-xL or Mcl-1 knockout mice. In this study, we further examine the underlying cellular mechanisms of generating tumors in apoptosis-prone liver. In cultured hepatocytes, the administration of ABT-737, a Bcl-xL/-2/-w inhibitor, led to production of reactive oxygen species (ROS) as well as activation of caspases. Mitochondria isolated from murine liver, upon administration of truncated-Bid, a proapoptotic Bcl-2 family protein, released cytochrome c and produced ROS, which was dependent on mitochondrial respiration. Hepatic apoptosis, regeneration, accumulation of oxidative damages, and tumorigenesis observed in hepatocyte-specific Mcl-1 knockout mice were substantially attenuated by further deficiency of Bax or Bid, suggesting that a balance of mitochondrial Bcl-2 family proteins governs generation of oxidative stress and other pathologies. Whole-exome sequencing clarified that C&gt;A/G&gt;T transversion, which is often caused by oxidative DNA damage in proliferating cells, was a frequently observed mutation pattern in liver tumors of Mcl-1 knockout mice. The administration of antioxidant L-N-acetylcysteine did not affect apoptosis, compensatory regeneration, or fibrotic responses but significantly reduced oxidative DNA damage and incidence and multiplicity of live tumors in Mcl-1 knockout mice. In conclusion, activation of the mitochondrial apoptotic pathway in hepatocytes accumulates intracellular oxidative damages, leading to liver tumorigenesis, independently of liver regeneration or fibrosis. This study supports a concept that antioxidant therapy may be useful for suppressing liver carcinogenesis in patients with chronic liver disease. Cancer Prev Res; 8(8); 693–701. ©2015 AACR.</jats:p>

収録刊行物

  • Cancer Prevention Research

    Cancer Prevention Research 8 (8), 693-701, 2015-08-01

    American Association for Cancer Research (AACR)

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