PubMed:11839683
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/11839683","sourcedb":"PubMed","sourceid":"11839683","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/11839683","text":"Protein kinase A RIalpha antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation.\nIt has been shown that expression of the RIalpha 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 RIalpha has a role in neoplastic cell growth in vitro and in vivo. In the present study, we have investigated the sequence- and target-specific effects of exogenous RIalpha 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 RIalpha antisense, RNA/DNA mixed backbone ODN exerts a reduction in RIalpha expression at both the mRNA and protein levels, up-regulation of both the RIIbeta 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 RIalpha antisense ODNs, which differed in sequence or chemical modification, promoted a sequence- and target-specific reduction in RIalpha protein levels and inhibited tumor growth in nude mice. These results demonstrate that in a sequence-specific manner, RIalpha antisense, via efficient depletion of the growth stimulatory molecule RIalpha, induces growth inhibition, apoptosis, and phenotypic (cell morphology) changes, providing an innovative approach to combat hormone-insensitive prostate cancer cell growth.","tracks":[{"project":"CoMAGC","denotations":[{"id":"T1","span":{"begin":1783,"end":1818},"obj":"Gene"},{"id":"E2","span":{"begin":1766,"end":1775},"obj":"Negative_regulation"},{"id":"T2","span":{"begin":1963,"end":1978},"obj":"prostate cancer"}],"relations":[{"id":"R1","pred":"themeOf","subj":"T1","obj":"E2"},{"id":"R3","pred":"CGE-decreased","subj":"T1","obj":"T2"},{"id":"R4","pred":"CCS-cancerTOnormal","subj":"T1","obj":"T2"},{"id":"R5","pred":"PT-causality","subj":"T1","obj":"T2"},{"id":"R3","pred":"IGE-unidentifiable","subj":"T1","obj":"T2"}],"attributes":[{"subj":"T1","pred":"source","obj":"CoMAGC"},{"subj":"E2","pred":"source","obj":"CoMAGC"},{"subj":"T2","pred":"source","obj":"CoMAGC"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"CoMAGC","color":"#e293ec","default":true}]}]}}