Antisense depletion of RIα subunit of protein kinase A induces apoptosis and growth arrest in human breast cancer cells

Abstract

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.

A genomic-scale view of the cAMP response element-enhancer decoy: A tumor target-based genetic tool

“…These molecular effects were consistent with the growth inhibition and the reverted phenotype observed in transformed cells treated with these ODNs (20)(21)(22)(23)(24). Importantly, the cluster analysis observed in the absence (Fig.…”

CpG Immunomer DNA Enhances Antisense Protein Kinase A RIα Inhibition of Multidrug-Resistant Colon Carcinoma Growth in Nude Mice: Molecular Basis for Combinatorial Therapy

“…The RIa antisense oligodeoxynucleotide seemed to restrain tumor cell growth by inhibiting tyrosine kinase signaling, cell cycle deregulation, and induction of apoptosis and differentiation (25, 36 -40). Treatment with RIa antisense of different types of cancer cell lines (MCF-7 hormone dependent, MDA-MB-231 hormone-independent breast cancer, PC3M hormoneinsensitive prostate cancer) induces growth inhibition through apoptotic pathway (25,38,40). Along with these data, our present study shows that antisense RIa inhibits HCT-15 multidrug resistant tumor growth in nude mice involving modulation of apoptotic proteins, such as Bcl-2, Bax, and Bak.…”

Dual Anticancer Activity of 8-Cl-cAMP: Inhibition of Cell Proliferation and Induction of Apoptotic Cell Death

“…Initially, 8-Cl-cAMP was reported to inhibit cancer cell proliferation without inducing cell death (10). However, recent reports showed that 8-Cl-cAMP induces apoptotic cell death as well in cancer cells (24,25). Therefore, we assumed that both the inhibition of cell proliferation and the apoptotic cell death may constitute 8-Cl-cAMP-induced growth inhibition.…”