title: PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma.
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.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Watcharin
authors.initials: W
authors.lastname: Loilome
authors.forename: Sirinun
authors.initials: S
authors.lastname: Juntana
authors.forename: Nisana
authors.initials: N
authors.lastname: Namwat
authors.forename: Vajarabhongsa
authors.initials: V
authors.lastname: Bhudhisawasdi
authors.forename: Anucha
authors.initials: A
authors.lastname: Puapairoj
authors.forename: Banchob
authors.initials: B
authors.lastname: Sripa
authors.forename: Masanao
authors.initials: M
authors.lastname: Miwa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D012333:RNA, Messenger