Increased expression of the RIα subunit of the cAMP-dependent protein kinase A is associated with advanced stage ovarian cancer

Abstract

SummaryThe primary element in the cAMP signal transduction pathway is the cAMP-dependent protein kinase (PKA). Expression of the RIα subunit of type I PKA is elevated in a variety of human tumours and cancer cell lines. The purpose of this study was to assess the prognostic importance of RIα expression in patients with ovarian cancer. We have evaluated the expression of RIα in a panel of human ovarian tumours (n = 40) and five human ovarian cancer cell lines using quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The human ovarian cell lines OAW42 and OTN14 express high endogenous levels of RIα mRNA and protein (at significantly higher mRNA levels than high tissue expressors, P < 0.05). The ovarian cell line A2780 expresses low endogenous levels of RIα mRNA and protein (also at higher mRNA levels than low tissue expressors, P < 0.05). Quantitative RT-PCR revealed no significant difference in RIα mRNA expression between different ovarian histological subtypes in this study. No associations were found between RIα mRNA expression and differentiation state. RIα mRNA expression was significantly associated with tumour stage (P = 0.0036), and this remained significant in univariate analysis (P = 0.0002). A trend emerged between RIα mRNA expression levels and overall survival in univariate analysis (P = 0.051), however, by multivariate analysis, stage remained the major determinant of overall survival (P = 0.0001). This study indicates that in ovarian epithelial tumours high RIα mRNA expression is associated with advanced stage disease. RIα expression may be of predictive value in ovarian cancer and may be associated with dysfunctional signalling pathways in this cancer type.

Phosphorylation of Claudin-3 at Threonine 192 by cAMP-dependent Protein Kinase Regulates Tight Junction Barrier Function in Ovarian Cancer Cells

“…2A also expressed regulatory subunits (data not shown), indicating the existence of functional PKA complexes in these cells. This is in agreement with previous reports showing a frequent activation of PKA in ovarian cancer (30,31). Claudin-3 expression was absent in non-malignant HOSE-B cells but found in most of the ovarian cancer lines.…”

“…PKA activation has been suggested to have a role in TJ disruption (32), and claudin-3 phosphorylation may represent one of the targets to achieve this physiological outcome. Interestingly, PKA is often activated in ovarian cancer (30,31). In addition, our unpublished work 2 suggests that claudin overexpression in ovarian cancer cells may contribute to an increase in invasion and survival of these cells, mediated at least in part through the breakdown of TJs.…”

Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

“…This overexpression of R1A has also been associated with poor prognosis in patients with ovarian cancer (35). The stimulation of cell proliferation by silencing of PRKAR2B in the mouse adrenocortical cell line Y1 has been reported recently (31).…”

Nuclear translocation of the catalytic subunit of protein kinase A induced by an antisense oligonucleotide directed against the RIα regulatory subunit

“…However, experimental evidence has implicated the R subunits in the regulation of cell proliferation or di erentiation (Cho-Chung, 1990), and increased RI expression has been observed in many primary human tumors (Bold et al, 1994;Bradbury et al, 1994;McDaid et al, 1999;Miller et al, 1993a,b;Simpson et al, 1996;Young et al, 1995). A site-selective cAMP analog that selectively downregulates RIa also inhibits the growth of human carcinomas, ®brosarcomas, and leukemias in vitro and in vivo .…”