2. Academic Validation
  3. Protein phosphatase 5 promotes hepatocarcinogenesis through interaction with AMP-activated protein kinase

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.
Yao-Li Chen 1,  Man-Hsin Hung 2,  Pei-Yi Chu 3,  Tzu-I Chao 4,  Ming-Hsien Tsai 5,  Li-Ju Chen 5,  Yung-Jen Hsiao 5,  Chih-Ting Shih 5,  Feng-Shu Hsieh 6,  Kuen-Feng Chen 7
Affiliations

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.

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