Protein phosphatase 5 promotes hepatocarcinogenesis through interaction with AMP-activated protein kinase

• Published in: Biochemical pharmacology 2017-08, Vol.138, p.49-60
• Main Authors: Chen, Yao-Li, Hung, Man-Hsin, Chu, Pei-Yi, Chao, Tzu-I, Tsai, Ming-Hsien, Chen, Li-Ju, Hsiao, Yung-Jen, Shih, Chih-Ting, Hsieh, Feng-Shu, Chen, Kuen-Feng
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - chemistry; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Carcinogenesis; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Enzyme Activation - drug effects; Enzyme Induction; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Gene Deletion; HCC; HEK293 Cells; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Mice, Nude; Neoplasm Proteins - agonists; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Staging; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphatase inhibitor; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; PP5; Protein Tyrosine Phosphatases, Non-Receptor - antagonists & inhibitors; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; Random Allocation; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; RNA Interference; Survival Analysis; Tumor Burden - drug effects
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2017.05.010

[Display omitted] The serine-threonine protein phosphatase family members are known as critical regulators of various cellular functions, such as survival and transformation. Growing evidence suggests that pharmacological manipulation of phosphatase activity exhibits therapeutic benefits. Ser/Thr protein phosphatase 5 (PP5) is known to participate in glucocorticoid receptor (GR) and stress-induced signaling cascades that regulate cell growth and apoptosis, and has been shown to be overexpressed in various human malignant diseases. However, the role of PP5 in hepatocellular carcinoma (HCC) and whether PP5 may be a viable therapeutic target for HCC treatment are unknown. Here, by analyzing HCC clinical samples obtained from 215 patients, we found that overexpression of PP5 is tumor specific and associated with worse clinical outcomes. We further characterized the oncogenic properties of PP5 in HCC cells. Importantly, both silencing of PP5 with lentiviral-mediated short hairpin RNA (shRNA) and chemical inhibition of PP5 phosphatase activity using the natural compound cantharidin/norcantharidin markedly suppressed the growth of HCC cells and tumors in vitro and in vivo. Moreover, we identified AMP-activated protein kinase (AMPK) as a novel downstream target of oncogenic PP5 and demonstrated that the antitumor mechanisms underlying PP5 inhibition involve activation of AMPK signaling. Overall, our results establish a pathological function of PP5 in hepatocarcinogenesis via affecting AMPK signaling and suggest that PP5 inhibition is an attractive therapeutic approach for HCC.