Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies

Pei Ming Yang, Yuan Ling Liu, Yi Chu Lin, Chia Tung Shun, Ming Shiang Wu, Ching Chow Chen

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)

Abstract

Preclinical and clinical studies have shown that statins, the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors with cholesterol-lowering properties, exhibited anticancer effects. However, the underlying mechanisms remain ill defined. In this study, we showed that atorvastatin could inhibit the growth of hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells via induction of apoptosis. Atorvastatin also induced autophagy that is a physiologic process involved in the turnover of intracellular organelles. Atorvastatin-induced autophagy was found to be inhibited by AMP-activated protein kinase (AMPK) small interfering RNA. Examination of HCC patients showed the positive correlation between AMPK activity and autophagic marker (beclin-1). Atorvastatin-induced AMPK activation could induce p21 expression, which was also positively correlated with beclin-1 expression in CRC patients. AMPK/p21 signaling caused endoplasmic reticulum (ER) stress response leading to the induction of autophagy. Inhibition of autophagy by an autophagic inhibitor bafilomycin A1 or genetic knockout of autophagy-related gene 5 enhanced atorvastatin-induced cytotoxicity and apoptosis. In summary, activation of AMPK by atorvastatin enhances p21 expression and ER stress response, leading to autophagy, which promotes survival of cancer cells. Combinations of atorvastatin with bafilomycin A1 provide a novel and promising strategy to improve the treatment of digestive malignancies.

Original languageEnglish
Pages (from-to)7699-7709
Number of pages11
JournalCancer Research
Volume70
Issue number19
DOIs
Publication statusPublished - Oct 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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