Compensatory stabilization of RII(β) protein, cell cycle deregulation, and growth arrest in colon and prostate carcinoma cells by antisense-directed down-regulation of protein kinase A RI(α) protein

M. Nesterova, K. Noguchi, Y. G. Park, Nam Lee Youl Nam Lee, Y. S. Cho-Chung

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The cyclic AMP-dependent protein kinase (PKA) exists in two isoforms, PKA-I (type I) and PKA-II (type II), that contain an identical catalytic (C) subunit but distinct regulatory (R) subunits, RI and RII, respectively. Increased expression of RI(α)/PKA-I has been shown in human cancer cell lines, in primary tumors, in cells after transformation, and in cells upon stimulation of growth. We have shown previously that a single-injection RI(α) antisense treatment results in a reduction in RI(α) and PKA-I expression and sustained inhibition of human colon carcinoma growth in athymic mice (M. Nesterova and Y. S. Cho-Chung, Nat. Med., 1: 528-533, 1995). Growth inhibition accompanied reduction in RI(α)/PKA-I expression and compensatory increases in RII(β) protein and PKA-II(β), the RII(β)-containing holoenzyme. Here, we report that these in vivo findings are consistent with observations made in cancer cells in culture. We demonstrate that the antisense depletion of RI(α) in cancer cells results in increased RII(β) protein without increasing the rate of RII(β) synthesis or RII(β) mRNA levels. Pulse-chase experiments revealed a 3-6-fold increase in the half-life of RII(β) protein in antisense-treated colon and prostate carcinoma cells with little or no change in the half-lives of RI(α), RII(α), and C(α) proteins. Compensation by RII(β) stabilization may represent a novel biochemical adaptation mechanism of the cell in response to sequence-specific loss of RI(α) expression, which leads to sustained down-regulation of PKA-I activity and inhibition of tumor growth.

Original languageEnglish
Pages (from-to)3434-3441
Number of pages8
JournalClinical Cancer Research
Volume6
Issue number9
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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