Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma

Ming Hung Hu, Tzu Ting Huang, Tzu I. Chao, Li Ju Chen, Yen Lin Chen, Ming Hsien Tsai, Chun Yu Liu, Jia Horng Kao, Kuen Feng Chen

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Background & Aims: Few molecules are currently verified to be actionable drug targets in cholangiocarcinoma (CCA). Serine/threonine protein phosphatase 5 (PP5) dysregulation is related to several malignancies. However, the role of PP5 in CCA is poorly defined. Methods: Colony and tumorsphere formation assays were conducted to establish the role of PP5 in CCA tumorigenesis. Cantharidin (CTD) and norcantharidin (NCTD), both potent PP5 inhibitors, were used in in vitro and in vivo experiments to validate the potential therapeutic role of PP5. Results: Increased cell growth, colony formation and tumorsphere formation were observed in PP5-overexpressing CCA cells, whereas PP5 knockdown by shRNA decreased cell growth and colony formation. Tumours from HuCCT1 xenograft-bearing mice treated with PP5-shRNA showed decreased growth and increased AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, CTD treatment decreased cell viability, reduced PP5 activity and enhanced AMPK phosphorylation in CCA cell lines. Overexpressing PP5 or enhancing PP5 activity suppressed AMPK phosphorylation and decreased CTD-induced cell death. Suppressing p-AMPK with siRNA or inhibitors also decreased CTD-induced cell death, suggesting a pivotal role for PP5-AMPK cascades in CCA. Immunoprecipitation revealed that PP5 interacted with AMPK. Importantly, treatment of HuCCT1 xenograft-bearing mice with NCTD, a CTD analogue with a lower systemic toxicity in vivo, suppressed PP5 activity, increased p-AMPK and reduced tumour volume. Conclusions: Protein phosphatase 5 negatively regulates AMPK phosphorylation and contributes to CCA aggressiveness; thus, PP5 may be a potential therapeutic target in CCA.

Original languageEnglish
Pages (from-to)2248-2259
Number of pages12
JournalLiver International
Volume38
Issue number12
DOIs
Publication statusPublished - Dec 2018
Externally publishedYes

Keywords

  • AMP-activated protein kinase
  • cantharidin
  • cholangiocarcinoma
  • protein phosphatase 5

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma'. Together they form a unique fingerprint.

Cite this