Protein kinase Calpha expression confers retinoic acid sensitivity on MDA-MB-231 human breast cancer cells.
Retinoic acid activation of retinoic acid receptor alpha (RARalpha) induces protein kinase Calpha (PKCalpha) expression and inhibits proliferation of the hormone-dependent T-47D breast cancer cell line. Retinoic acid has no effect on proliferation or PKCalpha expression in a hormone-independent, breast cancer cell line (MDA-MB-231). To test the role of PKCalpha in retinoic acid-induced growth arrest of human breast cancer cells we established MDA-MB-231 cell lines stably expressing PKCalpha. Constitutive expression of PKCalpha did not affect proliferation of MDA-MB-231 cells but did result in partial retinoic acid sensitivity. Retinoic acid treatment of PKCalpha-MDA-MB-231 cells decreased proliferation (by approximately 40%) and inhibited serum activation of MAP kinases and induction of c-fos. Similar results were seen in MDA-MB-231 cells in which transcription of the transfected PKCalpha cDNA was reversibly induced by isopropyl beta-d-thiogalactoside. Expression of RARalpha in PKCalpha expressing MDA-MB-231 cells resulted in even greater retinoic acid responses, as measured by effects on cell proliferation, inhibition of serum signaling, and transactivation of an RARE-CAT reporter plasmid. In summary, PKCalpha synergizes with activated RARalpha to disrupt serum growth factor signaling, ultimately arresting proliferation of MDA-MB-231 cells.
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Institute of Human Nutrition, Columbia University, New York, New York 10032, USA.
Talmage
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D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001798:Blood Proteins / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D011493:Protein Kinase C / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*
D000970:Antineoplastic Agents; D001798:Blood Proteins; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D007544:Isopropyl Thiogalactoside; D014212:Tretinoin; D004815:Epidermal Growth Factor; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium