Protein kinase A-Iα subunit-directed antisense inhibition of ovarian cancer cell growth: crosstalk with tyrosine kinase signaling pathway

Abstract

Expression of the RIa subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal growth factorrelated growth factors is activated. We have investigated the e ect of sequence-speci®c inhibition of RIa gene expression on ovarian cancer cell growth. We report that RIa antisense treatment results in a reduction in RIa expression and protein kinase A type I, and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF receptor, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimulated mitogen-activated protein kinase activities were reduced. Protein kinase A type I and EGF receptor levels were also reduced in cells overexpressing EGF receptor antisense cDNA. These results suggest that the antisense depletion of RIa leads to blockade of both the serinethreonine kinase and the tyrosine kinase signaling pathways resulting in arrest of ovarian cancer cell growth.

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 In addition, our unpublished work 2 suggests that claudin overexpression in ovarian cancer cells may contribute to an increase in invasion and survival of these cells, mediated at least in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.…”

Phosphorylation of Presenilin 1 at the Caspase Recognition Site Regulates Its Proteolytic Processing and the Progression of Apoptosis

“…Activation of (54, 55) PKC inhibits apoptosis in several cell types (51,56). Moreover, PKC is up-regulated in a wide range of cancers (51,57). However, also pro-apoptotic activities of PKC have been reported, and it is assumed that the different functions of this kinase in apoptosis might be exerted by distinct isoenzymes (51).…”

Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin–epithelin precursor (GEP), a prosurvival factor for ovarian cancer

“…PKA is the classical intracellular cAMP receptor and has been shown to be upregulated in a number of cancers, including ovarian cancer (Alper et al, 1999;Amsterdam et al, 1999;McDaid et al, 1999). Studies using a cAMP response element (CRE)-decoy in ovarian cancer cells have shown that the subset of genes activated by CRE are critical to controlling apoptosis, growth, and invasion (Alper et al, 1999).…”