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

• Published in: Experimental cell research 1997-11, Vol.237 (1), p.118-126
• Main Authors: Wu, Shujian, Zhang, Zhen-ping, Zhang, Dongmei, Soprano, Dianne Robert, Soprano, Kenneth J.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - toxicity; antisense, dominant negative RAR mutants; Cell Division - drug effects; Cell Nucleus - metabolism; Female; Humans; Isopropyl Thiogalactoside - pharmacology; Mice; Ovarian Neoplasms; Receptors, Retinoic Acid - biosynthesis; Receptors, Retinoic Acid - physiology; Recombinant Proteins - biosynthesis; Retinoic Acid Receptor alpha; retinoic acid receptors; Retinoid X Receptors; RNA, Antisense - metabolism; RNA, Messenger - metabolism; Transcription Factors - biosynthesis; Transcription Factors - physiology; Transcription, Genetic; Transfection; Tretinoin - toxicity; Tumor Cells, Cultured
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1006/excr.1997.3769

We wished to determine the effect of altering the levels or functional activity of retinoid receptors, in particular retinoic acid receptor-α (RAR-α) and retinoid X receptor-α (RXR-α) 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-β(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-α, RXR-α, or both RAR-α and RXR-α 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-α alone or RXR-α 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-α and RXR-α were reduced. These results demonstrate the importance of both retinoid nuclear receptors and retinoid-X receptors in general, and RAR-α and RXR-α in particular, as mediators of ovarian carcinoma cell growth inhibition by retinoids.