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

Yao-Li Chen; Man-Hsin Hung; Pei-Yi Chu; Tzu-I Chao; Ming-Hsien Tsai; Li-Ju Chen; Yung-Jen Hsiao; Chih-Ting Shih; Feng-Shu Hsieh; Kuen-Feng Chen

doi:10.1016/j.bcp.2017.05.010

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

Biochem Pharmacol. 2017 Aug 15:138:49-60. doi: 10.1016/j.bcp.2017.05.010. Epub 2017 May 19.

Authors

Yao-Li Chen¹, Man-Hsin Hung², Pei-Yi Chu³, Tzu-I Chao⁴, Ming-Hsien Tsai⁵, Li-Ju Chen⁵, Yung-Jen Hsiao⁵, Chih-Ting Shih⁵, Feng-Shu Hsieh⁶, Kuen-Feng Chen⁷

Affiliations

¹ School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan.
² Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
³ Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
⁴ Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan.
⁵ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: fengshu0430@gmail.com.
⁷ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: kfchen1970@ntu.edu.tw.

PMID: 28528695
DOI: 10.1016/j.bcp.2017.05.010

Abstract

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.

Keywords: AMPK; Carcinogenesis; HCC; PP5; Phosphatase inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / chemistry
AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism*
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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
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*
Phosphoprotein Phosphatases / antagonists & inhibitors
Phosphoprotein Phosphatases / genetics
Phosphoprotein Phosphatases / metabolism*
Protein Tyrosine Phosphatases, Non-Receptor / antagonists & inhibitors
Protein Tyrosine Phosphatases, Non-Receptor / genetics
Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
RNA Interference
Random Allocation
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / metabolism
Survival Analysis
Tumor Burden / drug effects

Substances

Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
Enzyme Inhibitors
Neoplasm Proteins
Nuclear Proteins
Recombinant Fusion Proteins
norcantharidin
AMP-Activated Protein Kinases
Phosphoprotein Phosphatases
protein phosphatase 5
PTPN5 protein, human
Protein Tyrosine Phosphatases, Non-Receptor