Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies.
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.
Yang
Pei-Ming
PM
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Liu
Yuan-Ling
YL
Lin
Yi-Chu
YC
Shun
Chia-Tung
CT
Wu
Ming-Shiang
MS
Chen
Ching-Chow
CC
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000069059:Atorvastatin; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004067:Digestive System Neoplasms / Q000188:drug therapy*; D005260:Female; D045325:HCT116 Cells; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics
D050759:Cyclin-Dependent Kinase Inhibitor p21; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018942:Macrolides; D011758:Pyrroles; D034741:RNA, Small Interfering; C057620:bafilomycin A; D000069059:Atorvastatin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases