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

Ming-Hung Hu1,2,3, Tzu-Ting Huang4, Tzu-I Chao5

  • 1Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Liver International : Official Journal of the International Association for the Study of the Liver
|May 26, 2018
PubMed
Abstract

Insights

Protein phosphatase 5 (PP5) promotes cholangiocarcinoma (CCA) growth by inhibiting AMP-activated protein kinase (AMPK). Inhibiting PP5 with compounds like norcantharidin (NCTD) suppressed tumor growth, highlighting PP5 as a potential therapeutic target for CCA.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cholangiocarcinoma (CCA) has limited actionable drug targets.
  • Dysregulation of Serine/threonine protein phosphatase 5 (PP5) is implicated in various cancers.
  • The specific role of PP5 in CCA pathogenesis remains largely undefined.

Purpose of the Study:

  • To investigate the role of PP5 in CCA tumorigenesis.
  • To evaluate PP5 inhibitors as a potential therapeutic strategy for CCA.
  • To elucidate the molecular mechanisms underlying PP5's function in CCA.

Main Methods:

  • Utilized colony and tumorsphere formation assays to assess CCA cell growth.
  • Employed PP5 inhibitors Cantharidin (CTD) and norcantharidin (NCTD) in vitro and in vivo.
  • Performed PP5 overexpression and knockdown studies, including shRNA-mediated knockdown in xenograft models.
  • Investigated the interaction between PP5 and AMP-activated protein kinase (AMPK) via immunoprecipitation.

Main Results:

  • PP5 overexpression increased CCA cell growth and colony formation, while PP5 knockdown reduced these.
  • PP5 knockdown in xenografts decreased tumor growth and increased AMPK phosphorylation.
  • CTD treatment reduced CCA cell viability, PP5 activity, and enhanced AMPK phosphorylation.
  • PP5 negatively regulates AMPK phosphorylation; PP5 inhibition or AMPK suppression affected CTD-induced cell death.
  • NCTD treatment in vivo suppressed PP5, increased p-AMPK, and reduced tumor volume in CCA xenografts.

Conclusions:

  • Protein phosphatase 5 (PP5) negatively regulates AMPK phosphorylation.
  • PP5 contributes to CCA aggressiveness and tumorigenesis.
  • PP5 represents a promising therapeutic target for cholangiocarcinoma treatment.
Keywords:
AMP-activated protein kinasecantharidincholangiocarcinomaprotein phosphatase 5

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