Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma
Ming-Hung Hu
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Division of Hematology and Oncology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan
School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
Search for more papers by this authorTzu-Ting Huang
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
Search for more papers by this authorTzu-I Chao
Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan
Search for more papers by this authorLi-Ju Chen
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorYen-Lin Chen
Department of Pathology, Cardinal Tien Hospital, New Taipei City, Taiwan
Search for more papers by this authorMing-Hsien Tsai
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorCorresponding Author
Chun-Yu Liu
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
School of Medicine, National Yang-Ming University, Taipei, Taiwan
Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Correspondence
Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Jia-Horng Kao, Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Chun-Yu Liu, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jia-Horng Kao
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Correspondence
Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Jia-Horng Kao, Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Chun-Yu Liu, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Kuen-Feng Chen
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
Correspondence
Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Jia-Horng Kao, Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Chun-Yu Liu, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
Search for more papers by this authorMing-Hung Hu
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Division of Hematology and Oncology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan
School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
Search for more papers by this authorTzu-Ting Huang
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
Search for more papers by this authorTzu-I Chao
Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan
Search for more papers by this authorLi-Ju Chen
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorYen-Lin Chen
Department of Pathology, Cardinal Tien Hospital, New Taipei City, Taiwan
Search for more papers by this authorMing-Hsien Tsai
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorCorresponding Author
Chun-Yu Liu
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
School of Medicine, National Yang-Ming University, Taipei, Taiwan
Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Correspondence
Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Jia-Horng Kao, Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Chun-Yu Liu, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jia-Horng Kao
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Correspondence
Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Jia-Horng Kao, Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Chun-Yu Liu, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Kuen-Feng Chen
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
Correspondence
Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Jia-Horng Kao, Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan.
Email: [email protected]
and
Chun-Yu Liu, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
Search for more papers by this authorFunding information
This study was supported by a grant from Cardinal Tien Hospital (CTH-104-2-2A02).
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.
CONFLICT OF INTEREST
All authors do not have any disclosures to report.
Supporting Information
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