Antisense depletion of RIalpha subunit of protein kinase A induces apoptosis and growth arrest in human breast cancer cells.
In recent years, several laboratories have explored the possibility of using antisense oligodeoxynucleotides for specific manipulation of gene expression leading to cancer treatment. The enhanced expression of the RIalpha subunit of cyclic AMP-dependent protein kinase type I (PKA-I) has been correlated with cancer cell growth. In the present study, the effects of an antisense oligodeoxynucleotide targeted against RIalpha subunit of PKA-I on growth inhibition and apoptosis in MDA-MB-231 human breast cancer cells were investigated. The growth inhibitory effects of RIalpha antisense oligodeoxynucleotide correlated with a decrease in the RIalpha mRNA and protein levels. The growth inhibition was accompanied by changes in the cell cycle phase distribution, cell morphology, cleavage of poly (ADP-ribose) polymerase (PARP), and appearance of apoptotic nuclei. By comparison, mismatched control oligodeoxynucleotide had no effect. On the basis of these results, it can be suggested that the RIalpha antisense oligodeoxynucleotide, which efficiently depletes the growth stimulatory RIalpha and induces apoptosis/differentiation, could be used as a therapeutic agent for breast cancer treatment.
Cellular Biochemistry Section, Laboratory of Tumor and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
R K
RK
Srivastava
A R
AR
Srivastava
Y G
YG
Park
S
S
Agrawal
Y S
YS
Cho-Chung
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D016376:Oligonucleotides, Antisense; C517834:PRKAR1A protein, human; D013873:Thionucleotides; D017868:Cyclic AMP-Dependent Protein Kinases