Antisense DNA-targeting protein kinase A-RIA subunit: a novel approach to cancer treatment.
Enhanced expression of the RIa subunit of cAMP-dependent protein kinase type I (PKA-I) has been shown during carcinogenesis, in human cancer cell lines and in primary tumors. We demonstrate that the sequence-specific inhibition of RIa gene expression by antisense oligonucleotides results in the differentiation of leukemia cells and growth arrest of cancer cells of epithelial origin and tumors in mice. The loss of RI by the antisense results in rapid increase in the half-life of the competitor molecule, RII protein, via its stabilization in a holoenzyme complex (PKA-II) that insures depletion of PKA-I and sustained inhibition of tumor growth. RI antisense, which restrains tumor cell growth by turning on the signals for blockade of tumor cell survival, namely blockade of the tyrosine kinase signaling, cell cycle deregulation and apoptosis, provides a single gene-targeting approach to treatment of cancer.
Cho-Chung
Y S
YS
Cellular Biochemistry Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892, USA.
Nesterova
M
M
Pepe
S
S
Lee
G R
GR
Noguchi
K
K
Srivastava
R K
RK
Srivastava
A R
AR
Alper
O
O
Park
Y G
YG
Lee
Y N
YN
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D016373:DNA, Antisense / Q000235:genetics / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D016373:DNA, Antisense; C517834:PRKAR1A protein, human; C517819:PRKAR2A protein, human; C517837:PRKAR2B protein, human; C517835:Prkar1a protein, mouse; C517821:Prkar2a protein, mouse; C517838:Prkar2b protein, mouse; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases