2. Academic Validation
  3. Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma

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

  • Liver Int. 2018 Dec;38(12):2248-2259. doi: 10.1111/liv.13887.
Ming-Hung Hu 1 2 3,  Tzu-Ting Huang 4,  Tzu-I Chao 5,  Li-Ju Chen 6,  Yen-Lin Chen 7,  Ming-Hsien Tsai 6,  Chun-Yu Liu 4 8 9,  Jia-Horng Kao 1 10,  Kuen-Feng Chen 6 11
Affiliations

Affiliations

  • 1 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 2 Division of Hematology and Oncology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan.
  • 3 School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
  • 4 Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan.
  • 5 Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan.
  • 6 Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
  • 7 Department of Pathology, Cardinal Tien Hospital, New Taipei City, Taiwan.
  • 8 School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 9 Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 10 Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • 11 National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
PMID: 29797403 DOI: 10.1111/liv.13887
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.

Keywords

AMP-activated protein kinase; cantharidin; cholangiocarcinoma; protein phosphatase 5.

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