Reduction of both RAR and RXR levels is required to maximally alter sensitivity of CA-OV3 ovarian tumor cells to growth suppression by all-trans-retinoic acid.
We wished to determine the effect of altering the levels or functional activity of retinoid receptors, in particular retinoic acid receptor-alpha (RAR-alpha) and retinoid X receptor-alpha (RXR-alpha) on the growth sensitivity of ovarian tumor cells to all-trans-retinoic acid (all-trans-RA). We found that CA-OV3 cells could be made resistant to all-trans-RA growth inhibition by overexpressing RAR-beta(R269Q), an efficient dominant negative mutant which inhibits the function of all RAR subtypes. Antisense technology was then used to prepare stable transfectants of the retinoid-sensitive ovarian carcinoma cell line CA-OV3 in which expression of RAR-alpha, RXR-alpha, or both RAR-alpha and RXR-alpha was reduced. The effect of all-trans-RA on ovarian tumor cell growth was determined by MTT assay, autoradiographic analysis of DNA synthesis, and anchorage-independent colony formation in soft agar. Our results show that cell lines expressing reduced levels of either RAR-alpha alone or RXR-alpha alone exhibited a small decrease in sensitivity to growth inhibition by all-trans-RA. However, maximum RA resistance was obtained in cell lines in which the levels of both RAR-alpha and RXR-alpha were reduced. These results demonstrate the importance of both retinoid nuclear receptors and retinoid-X receptors in general, and RAR-alpha and RXR-alpha in particular, as mediators of ovarian carcinoma cell growth inhibition by retinoids.
Wu
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Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Zhang
Z P
ZP
Zhang
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Soprano
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Soprano
K J
KJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006801:Humans; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D051379:Mice; D010051:Ovarian Neoplasms; D016372:RNA, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C000607071:RARA protein, human; D016372:RNA, Antisense; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D007544:Isopropyl Thiogalactoside; D014212:Tretinoin