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 language | English |
|---|---|
| Pages (from-to) | 607-614 |
| Number of pages | 8 |
| Journal | Clinical Cancer Research |
| Volume | 8 |
| Issue number | 2 |
| Publication status | Published - 2002 Jan 1 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Protein kinase a RIα antisense inhibition of PC3m prostate cancer cell growth
T2 - Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation
AU - Cho, Yee Sook
AU - Kim, Meyoung-Kon
AU - Tan, Langzhu
AU - Srivastava, Rakesh
AU - Agrawal, Sudhir
AU - Cho-Chung, Yoon S.
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036188072&partnerID=8YFLogxK
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M3 - Article
VL - 8
SP - 607
EP - 614
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 2
ER -