PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma

Watcharin Loilome, Sirinun Juntana, Nisana Namwat, Vajarabhongsa Bhudhisawasdi, Anucha Puapairoj, Banchob Sripa, Masanao Miwa, Hideyuki Saya, Gregory J. Riggins, Puangrat Yongvanit

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The protein kinase A regulatory subunit 1 alpha (PRKAR1A/PKAI) pathway is overexpressed in varieties of tumors and cancer cell lines including cholangiocarcinoma (CCA), although its role in CCA growth modulation is unclear. In our study, we evaluated the effect of PRKAR1A/PKAI targeting on CCA cell proliferation. Real-time PCR demonstrated an increased mRNA expression of PRKAR1A/PKAI, whereas protein kinase A regulatory subunit 2 beta (PRKAR2B/PKAII) was downregulated in human CCA tissues and CCA cell lines. Immunohistochemistry of human CCA tissues revealed increased PRKAR1A with decreased PRKAR2B protein expression. Moreover, CCA cell lines showed abundantly expressed PRKAR1A, while lacking PRKAR2B expression. Silencing PRKAR1A expression induced growth inhibition and apoptosis of CCA cells, with an associated decrease in mitogen-activated protein kinases, PI3K/Akt, JAK/STAT and Wnt/β-catenin pathway signaling. The inhibition of PKA using a PKA inhibitor and cAMP analogs also led to a significant cell growth inhibition. In conclusion, our study reports the overexpression as well as molecular mechanisms by which PRKAR1A/PKA regulates human CCA cell growth. Importantly, abrogation of gene expression caused significant CCA cell growth inhibition, oncogenic signaling and coupled apoptosis induction, suggesting PRKAR1A's potential as a drug target for CCA therapy.

Original languageEnglish
Pages (from-to)34-44
Number of pages11
JournalInternational Journal of Cancer
Volume129
Issue number1
DOIs
Publication statusPublished - 2011 Jul 1

Fingerprint

Cholangiocarcinoma
Therapeutics
Growth
Cyclic AMP-Dependent Protein Kinases
Apoptosis
Cell Line
Catenins
Wnt Signaling Pathway
Mitogen-Activated Protein Kinases
Tumor Cell Line
Phosphatidylinositol 3-Kinases
Real-Time Polymerase Chain Reaction
Down-Regulation
Immunohistochemistry
Cell Proliferation
Gene Expression

Keywords

  • cAMP-dependent protein kinase
  • cholangiocarcinoma
  • protein kinase A regulatory subunit 1 alpha

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Loilome, W., Juntana, S., Namwat, N., Bhudhisawasdi, V., Puapairoj, A., Sripa, B., ... Yongvanit, P. (2011). PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma. International Journal of Cancer, 129(1), 34-44. https://doi.org/10.1002/ijc.25646

PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma. / Loilome, Watcharin; Juntana, Sirinun; Namwat, Nisana; Bhudhisawasdi, Vajarabhongsa; Puapairoj, Anucha; Sripa, Banchob; Miwa, Masanao; Saya, Hideyuki; Riggins, Gregory J.; Yongvanit, Puangrat.

In: International Journal of Cancer, Vol. 129, No. 1, 01.07.2011, p. 34-44.

Research output: Contribution to journalArticle

Loilome, W, Juntana, S, Namwat, N, Bhudhisawasdi, V, Puapairoj, A, Sripa, B, Miwa, M, Saya, H, Riggins, GJ & Yongvanit, P 2011, 'PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma', International Journal of Cancer, vol. 129, no. 1, pp. 34-44. https://doi.org/10.1002/ijc.25646
Loilome, Watcharin ; Juntana, Sirinun ; Namwat, Nisana ; Bhudhisawasdi, Vajarabhongsa ; Puapairoj, Anucha ; Sripa, Banchob ; Miwa, Masanao ; Saya, Hideyuki ; Riggins, Gregory J. ; Yongvanit, Puangrat. / PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma. In: International Journal of Cancer. 2011 ; Vol. 129, No. 1. pp. 34-44.
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abstract = "The protein kinase A regulatory subunit 1 alpha (PRKAR1A/PKAI) pathway is overexpressed in varieties of tumors and cancer cell lines including cholangiocarcinoma (CCA), although its role in CCA growth modulation is unclear. In our study, we evaluated the effect of PRKAR1A/PKAI targeting on CCA cell proliferation. Real-time PCR demonstrated an increased mRNA expression of PRKAR1A/PKAI, whereas protein kinase A regulatory subunit 2 beta (PRKAR2B/PKAII) was downregulated in human CCA tissues and CCA cell lines. Immunohistochemistry of human CCA tissues revealed increased PRKAR1A with decreased PRKAR2B protein expression. Moreover, CCA cell lines showed abundantly expressed PRKAR1A, while lacking PRKAR2B expression. Silencing PRKAR1A expression induced growth inhibition and apoptosis of CCA cells, with an associated decrease in mitogen-activated protein kinases, PI3K/Akt, JAK/STAT and Wnt/β-catenin pathway signaling. The inhibition of PKA using a PKA inhibitor and cAMP analogs also led to a significant cell growth inhibition. In conclusion, our study reports the overexpression as well as molecular mechanisms by which PRKAR1A/PKA regulates human CCA cell growth. Importantly, abrogation of gene expression caused significant CCA cell growth inhibition, oncogenic signaling and coupled apoptosis induction, suggesting PRKAR1A's potential as a drug target for CCA therapy.",
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