Upregulation of AMPK by 4‐O‐methylascochlorin promotes autophagy via the HIF‐1α expression

• Published in: Journal of cellular and molecular medicine Vol. 22; no. 12; pp. 6345 - 6356
• Main Authors: Seok, Ji‐Young, Jeong, Yun‐Jeong, Hwang, Soon‐Kyung, Kim, Cheorl‐Ho, Magae, Junji, Chang, Young‐Chae
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-12-2018; John Wiley and Sons Inc
• Subjects: 4‐O‐methylascochlorin; Adenosine diphosphate; AMP; AMPK; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Apoptosis; Apoptosis - drug effects; Ascomycota - chemistry; Autophagy; Autophagy - drug effects; BNIP3; BNIP3 protein; Caspase; Cell Hypoxia - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Fungi; Gene Expression Regulation, Neoplastic - drug effects; HIF‐1α; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Kinases; Leukemia; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Membrane Proteins - genetics; Microtubule-Associated Proteins - genetics; Molecular modelling; Original; Phagocytosis; Phenols; Phosphorylation; Phosphorylation - drug effects; Protein expression; Protein kinase; Proteins; Proto-Oncogene Proteins - genetics; Rapamycin; Ribose; Signal transduction; Signal Transduction - drug effects; siRNA; Terpenes - chemistry; Terpenes - pharmacology; TOR protein; TOR Serine-Threonine Kinases - genetics; Transcriptional Activation - drug effects; Up-regulation; AMPK; 4-O-methylascochlorin; HIF-1α; autophagy; BNIP3
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.13933

4‐O‐methylascochlorin (MAC) is a derivative of ascochlorin, a prenyl‐phenol compound antibiotic isolated from the fungus Ascochyta viciae. MAC induces caspase/poly (ADP‐ribose) polymerase‐mediated apoptosis in leukemia cells. However, the effects of MAC on autophagy in cancer cells and the underlying molecular mechanisms remain unknown. Here, we show that MAC induces autophagy in lung cancer cells. MAC significantly induced the expression of autophagy marker proteins including LC3‐II, Beclin1, and ATG7. MAC promoted AMP‐activated protein kinase (AMPK) phosphorylation and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream signalling proteins P70S6K and 4EBP1. The AMPK activator AICAR upregulated LC3‐II expression through the AMPK/mTOR pathway similar to the effects of MAC. MAC‐induced LC3‐II protein expression was slightly reduced in AMPK siRNA transfected cells. MAC upregulated hypoxia‐inducible factor‐1α (HIF‐1α) and BNIP3, which are HIF‐1α‐dependent autophagic proteins. Treatment with CoCl2, which mimics hypoxia, induced autophagy similar to the effect of MAC. The HIF‐1α inhibitor YC‐1 and HIF‐1α siRNA inhibited the MAC‐induced upregulation of LC3‐II and BNIP3. These results suggest that MAC induces autophagy via the AMPK/mTOR signalling pathway and by upregulating HIF‐1α and BNIP3 protein expression in lung cancer cells.