Protein kinase a RIα antisense inhibition of PC3m prostate cancer cell growth

Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation

Yee Sook Cho, Meyoung-Kon Kim, Langzhu Tan, Rakesh Srivastava, Sudhir Agrawal, Yoon S. Cho-Chung

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

It has been shown that expression of the RIα subunit of cyclic AMP (cAMP)-dependent protein kinase is enhanced in human cancer cell lines, primary tumors, and cells after transformation. Using an antisense strategy, we have shown that RIα has a role in neoplastic cell growth in vitro and in vivo. In the present study, we have investigated the sequenceand target-specific effects of exogenous RIα antisense oligodeoxynucleotides (ODNs) and endogenous antisense gene on tumor growth, apoptosis, and cAMP signaling in androgen-insensitive prostate cancer cells, both in vitro and in nude mice. Here, we show that an RIα antisense, RNA/DNA mixed backbone ODN exerts a reduction in RIα expression at both the mRNA and protein levels, up-regulation of both the RIIβ subunit of cAMP-dependent protein kinase or protein kinase A and c-AMP-phosphodiesterase IV expression, and inhibition of cell growth. Growth inhibition was accompanied by changes in cell morphology and the appearance of apoptotic nuclei. In addition, Bcl-2 hyperphosphorylation; increase in the proapoptotic proteins Bax, Bak, and Bad; and Bad hypophosphorylation occurred in the antisense-treated cells. These effects of exogenously supplied antisense ODN mirrored those induced by endogenous antisense gene overexpression. The RIα antisense ODNs, which differed in sequence or chemical modification, promoted a sequence- and target-specific reduction in RIα protein levels and inhibited tumor growth in nude mice. These results demonstrate that in a sequence-specific manner, RIα antisense, via efficient depletion of the growth stimulatory molecule RIα, induces growth inhibition, apoptosis, and phenotypic (cell morphology) changes, providing an innovative approach to combat hormone-insensitive prostate cancer cell growth.

Original languageEnglish
Pages (from-to)607-614
Number of pages8
JournalClinical Cancer Research
Volume8
Issue number2
Publication statusPublished - 2002 Jan 1
Externally publishedYes

Fingerprint

Protein Kinases
Prostatic Neoplasms
Up-Regulation
Oligodeoxyribonucleotides
Growth
Cyclic AMP-Dependent Protein Kinases
Tumor Cell Line
Nude Mice
bcl-2 Homologous Antagonist-Killer Protein
bcl-Associated Death Protein
Antisense DNA
Type 4 Cyclic Nucleotide Phosphodiesterase
Apoptosis
Antisense RNA
bcl-2-Associated X Protein
Neoplasms
Adenosine Monophosphate
Cyclic AMP
Androgens
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Protein kinase a RIα antisense inhibition of PC3m prostate cancer cell growth : Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. / Cho, Yee Sook; Kim, Meyoung-Kon; Tan, Langzhu; Srivastava, Rakesh; Agrawal, Sudhir; Cho-Chung, Yoon S.

In: Clinical Cancer Research, Vol. 8, No. 2, 01.01.2002, p. 607-614.

Research output: Contribution to journalArticle

Cho, Yee Sook ; Kim, Meyoung-Kon ; Tan, Langzhu ; Srivastava, Rakesh ; Agrawal, Sudhir ; Cho-Chung, Yoon S. / Protein kinase a RIα antisense inhibition of PC3m prostate cancer cell growth : Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 2. pp. 607-614.
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