title: Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation.
abstract: Hepatocellular carcinoma (HCC) is the most common liver cancer and the third-leading cause of cancer death worldwide. Nilotinib is an orally available receptor tyrosine kinase inhibitor approved for chronic myelogenous leukemia. This study investigated the effect of nilotinib on HCC. Nilotinib did not induce cellular apoptosis. Instead, staining with acridine orange and microtubule-associated protein 1 light chain 3 revealed that nilotinib induced autophagy in a dose- and time-dependent manner in HCC cell lines, including PLC5, Huh-7, and Hep3B. Moreover, nilotinib up-regulated the phosphryaltion of AMP-activated kinase (AMPK) and protein phosphatase PP2A inactivation were detected after nilotinib treatment. Up-regulating PP2A activity suppressed nilotinib-induced AMPK phosphorylation and autophagy, suggesting that PP2A mediates the effect of nilotinib on AMPK phosphorylation and autophagy. Our data indicate that nilotinib-induced AMPK activation is mediated by PP2A, and AMPK activation and subsequent autophagy might be a major mechanism of action of nilotinib. Growth of PLC5 tumor xenografts in BALB/c nude mice was inhibited by daily oral treatment with nilotinib. Western blot analysis showed both increased phospho-AMPK expression and decreased PP2A activity in vivo. Together, our results reveal that nilotinib induces autophagy, but not apoptosis in HCC, and that the autophagy-inducing activity is associated with PP2A-regulated AMPK phosphorylation.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan.
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Yu
authors.forename: Chen-Si
authors.initials: CS
authors.lastname: Lin
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D011743:Pyrimidines; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2; C498826:nilotinib
keywords: AMP-activated Kinase (AMPK); Apoptosis; Autophagy; HCC; Nilotinib; Serine Threonine Protein Phosphatase; Tyrosine Protein Kinase (Tyrosine Kinase)