This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guo, X. Articles by Gudas, L. J Search for Related Content PubMed PubMed Citation Articles by Guo, X. Articles by Gudas, L. J

Reduced Levels of Retinyl Esters and Vitamin A in Human Renal Cancers¹

Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021 [X. G., L. J. G.]; Division of Hematology and Medical Oncology, Department of Medicine and the Department of Urology, Weill Medical College of Cornell University, New York, New York 10021 [D. M. N.]; Department of Neurobiology [A. R., D. B.], Brain Research Institute [D. B.], and Jules Stein Eye Institute [D. B.], School of Medicine, University of California, Los Angeles, California 90095; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 [R. R. R.]

Clinical and preclinical studies suggest that retinoids can inhibit the growth of a small percentage of human renal cancers (RCs), although the majority of RCs both in vitro and in vivo are retinoid resistant. Our recent studies indicate that the metabolism of retinol to retinyl esters is greatly reduced in human carcinoma cell lines of the oral cavity, skin, and breast as compared with their normal epithelial counterparts, suggesting that human carcinoma cells are retinoid deficient relative to normal epithelial cells. We considered whether retinoid resistance in RCs was related to an abnormality in retinoid metabolism. The metabolism of [³H]retinol and of [³H]retinoic acid (RA) was examined in RC cell lines and normal human kidney (NK) epithelial cells cultured in media, in RA, or in RA plus IFN-. The expression of LRAT (lecithin:retinol acyltransferase) was assessed by Northern and Western analysis. Retinol and retinyl ester levels were determined in tissue samples of normal human kidney and renal cell carcinoma. NK cells esterified all of the 50 nM [³H]retinol in which they were cultured. In contrast, six of the seven RC cell lines metabolized only trace amounts of [³H]retinol to [³H]retinyl esters. Consistent with this relative lack of [³H]retinol esterification by the tumor cells, the tumor cells exhibited LRAT transcripts of aberrantly low sizes relative to those in normal epithelial cells. Moreover, the NK cells expressed abundant levels of LRAT protein by Western analysis, whereas the RC cells did not express LRAT protein. When samples of human kidney tumor tissue were compared with samples of normal kidney tissue from patients who had undergone surgery for primary RC, the normal kidney tissues contained much higher levels of retinol and retinyl esters (approximately 0.5–2 µg/gram wet weight) than the tumor tissues in all seven patients examined. Culture of the RC lines in IFN- plus all-trans-RA, a combination therapy used clinically, resulted in higher intracellular levels of [³H]retinol and [³H]retinyl esters. The metabolism of [³H]RA was also examined in these RC lines versus NK cells. Although the NK epithelial cells metabolized [³H]RA, the majority of the RC lines metabolized [³H]RA at a much slower rate. Most of the RC lines metabolized only 10–30% of the 50 nM [³H]RA over 6 h of culture. These data indicate that RCs both in vitro and in vivo are retinol and retinyl ester deficient relative to the normal human kidney, and they suggest that the aberrant differentiation of the neoplastic renal cells results in part from a defect in retinoid metabolism.

This article has been cited by other articles:

				I. Nazarenko, R. Schafer, and C. Sers Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells J. Cell Sci., April 15, 2007; 120(8): 1393 - 1404. [Abstract] [Full Text] [PDF]

				X.-H. Tang, M.-J. Suh, R. Li, and L. J. Gudas Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid J. Lipid Res., January 1, 2007; 48(1): 165 - 176. [Abstract] [Full Text] [PDF]

				L. Liu and L. J. Gudas Disruption of the Lecithin:Retinol Acyltransferase Gene Makes Mice More Susceptible to Vitamin A Deficiency J. Biol. Chem., December 2, 2005; 280(48): 40226 - 40234. [Abstract] [Full Text] [PDF]

				X.-f. Wang, D. Z. Qian, M. Ren, Y. Kato, Y. Wei, L. Zhang, Z. Fansler, D. Clark, O. Nakanishi, and R. Pili Epigenetic Modulation of Retinoic Acid Receptor {beta}2 by the Histone Deacetylase Inhibitor MS-275 in Human Renal Cell Carcinoma Clin. Cancer Res., May 1, 2005; 11(9): 3535 - 3542. [Abstract] [Full Text] [PDF]

				S. E. Touma, J. S. Goldberg, P. Moench, X. Guo, S. K. Tickoo, L. J. Gudas, and D. M. Nanus Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model Clin. Cancer Res., May 1, 2005; 11(9): 3558 - 3566. [Abstract] [Full Text] [PDF]

				H. K. Biesalski and D. Nohr New Aspects in Vitamin A Metabolism: the Role of Retinyl Esters as Systemic and Local Sources for Retinol in Mucous Epithelia J. Nutr., December 1, 2004; 134(12): 3453S - 3457S. [Abstract] [Full Text] [PDF]

				M. G. Villani, V. Appierto, E. Cavadini, M. Valsecchi, S. Sonnino, R. W. Curley, and F. Formelli Identification of the Fenretinide Metabolite 4-Oxo-Fenretinide Present in Human Plasma and Formed in Human Ovarian Carcinoma Cells through Induction of Cytochrome P450 26A1 Clin. Cancer Res., September 15, 2004; 10(18): 6265 - 6275. [Abstract] [Full Text] [PDF]

				S. Boorjian, S. K. Tickoo, N. P. Mongan, H. Yu, D. Bok, R. R. Rando, D. M. Nanus, D. S. Scherr, and L. J. Gudas Reduced Lecithin: Retinol Acyltransferase Expression Correlates with Increased Pathologic Tumor Stage in Bladder Cancer Clin. Cancer Res., May 15, 2004; 10(10): 3429 - 3437. [Abstract] [Full Text] [PDF]

				H. C. Zhan, L. J. Gudas, D. Bok, R. Rando, D. M. Nanus, and S. K. Tickoo Differential Expression of the Enzyme That Esterifies Retinol, Lecithin:Retinol Acyltransferase, in Subtypes of Human Renal Cancer and Normal Kidney Clin. Cancer Res., October 15, 2003; 9(13): 4897 - 4905. [Abstract] [Full Text] [PDF]

				F. Formelli, T. Camerini, E. Cavadini, V. Appierto, M. G. Villani, A. Costa, G. De Palo, M. G. Di Mauro, and U. Veronesi Fenretinide Breast Cancer Prevention Trial: Drug and Retinol Plasma Levels in Relation to Age and Disease Outcome Cancer Epidemiol. Biomarkers Prev., January 1, 2003; 12(1): 34 - 41. [Abstract] [Full Text] [PDF]

				A. C. Ross Retinoid Production and Catabolism: Role of Diet in Regulating Retinol Esterification and Retinoic Acid Oxidation J. Nutr., January 1, 2003; 133(1): 291S - 296. [Abstract] [Full Text] [PDF]

				X. Guo, B. S. Knudsen, D. M. Peehl, A. Ruiz, D. Bok, R. R. Rando, J. S. Rhim, D. M. Nanus, and L. J. Gudas Retinol Metabolism and Lecithin:Retinol Acyltransferase Levels Are Reduced in Cultured Human Prostate Cancer Cells and Tissue Specimens Cancer Res., March 1, 2002; 62(6): 1654 - 1661. [Abstract] [Full Text] [PDF]