Proliferation of cells and expression of RARs, RXRs and HPV viral E6 and E7 proteins in cervical cancer cell lines after treatment with ATRA.
More details
Hide details
Jan Dlugosz University in Czestochowa, Institute of Chemistry, Environmental Protection and Biotechnology, Częstochowa, Poland
Adam Mickiewicz University, Institute of Experimental Biology, Department of Animal Physiology and Development, Poznań, Poland
Department of Gynecological Oncology and Gynecology, Medical University of Lublin, Lublin, Poland
Department of Obstetrics and Gynecology, Medical University of Lublin, Lublin, Poland
Adam Mickiewicz University, Institute of Experimental Biology, Department of Molecular Virology, Poznań, Poland
Anna Gozdzicka-Jozefiak   

Department of Molecular Virology, Umultowska 89, 61-614 Poznan, Poland
Ann Agric Environ Med. 2011;18(1):145–150
All-trans retinoic acid (ATRA) is considered to be a potential chemotherapeutic drug due to its capability to regulate cell growth and differentiation. The effects of ATRA on the proliferation of cells and gene regulation are mediated by retinoid receptors (RAR and RXR), which belong to the nuclear receptor superfamily of ligand- inducible transcription factors. ATRA can act either as a growth inhibitor or growth promoter, according to the functional state of retinoic receptors. Thus, we have established the effect of ATRA on the proliferation of cervical cancer cells line HeLa and CaSki and expression of retinoids receptors as well as the viral HPV oncogenic proteins E6 and E7. ATRA had no effect on proliferation CaSki cells, but it stimulated the growth of HeLa cells, which depended on the incubation time and the concentration of ATRA in cell culture. The overexpression of RAR alpha in HeLa cells after the administration of 10-7 mM ATRA was also observed 72 hours, and the decrease of CaSki by 60-90 percent. In the study of cervical cancer cell lines, the very low levels of other endogenous RAR and RXR receptors were observed. ATRA does not repress the expression of two viral oncoproteins E6 and E7 HPV16/18, which play a key role in carcinogenesis of the cervix. Our results support the suggestions that the cell response to vitamin A, and other retinoids in the diet, may depend on cell type, and that the cancer cells are differentially resistant to retinoids. Thus, despite the important biological functions of retinoids, the effects of retinoids in a supplementation in supra-physiological doses as well as their physiological action are difficult to define.
Ahn MJ, Langenfeld J, Moasser MM, Rusch V, Dmitrovsky E: Growth suppression of transformed human bronchial epithelial cells by all-trans retinoic acid occurs through specific retinoid receptors. Oncogene 1995, 11, 2357–2364.
Alvarez S, Germain P, Alvarez P, Rodriques-Barrios F, Gronemeyer H, de Leva AR: Structure, function and modulation of retinoic acid receptor beta, a tumor suppressor. Int J Biochem Cell Biol 2007, 39, 1406–1415.
Arce JD, Gockel-Krzikalla E, Rosl F: Retinoic acid receptor beta silences human papillomavirus-18 oncogene expression by induction of de novo methylation and heterochromatinization of the viral control region. J Biol Chem 2007, 282, 28520–28529.
Balmer JE, Blomhoff R: Gene expression regulation by retinoic acid. J Lipid Res 2002, 43, 1773–1808.
Benko S, Love JD, Beladi M, Schwabe JWR, Nagy L: Molecular determinants of the balance between co-repressor and co-activator recruitment to the retinoic acid receptor. J Biol Chem 2003, 278, 43797– 43806.
Bernard HU, Apt D: Transcriptional control and cell type specificity of HPV gene expression. Arch Dermatol 1994, 130, 210–215.
Bogos K, Renyi-Vamos F, Kovacs G, Tovari J, Dome B: Role of retinoic receptors in lung carcinogenesis. J Exp Clin Cancer Res 2008, 27, 1–7.
Bu P, Wan YI: Fenretinide-induced apoptosis of Huh-7 hepatocellular carcinoma is retinoic acid receptor beta dependent. BMC Cancer 2007, 7, 236, doi:10.1186/1471-2407-7-236.
Butz K, Hoppe-Seyler F: Transcriptional control of human papillomavirus (HPV) oncogene expression: composition of the HPV type 18 upstream regulatory region. J Virol 1993, 67, 6476–6486.
Clarke V, Germain P, Altucci L, Gronemeyer H: Retinoids: potential in cancer prevention and therapy. Expert Rev Mol Med 2004, 6, 1–23.
Evans TR, Kaye SB: Retinoids: present role and future potential. Br J Cancer 1999, 80, 1–8.
Faluhelyi Z, Roder I, Csejtey A, Turing SK, Ember IA, Arany I: All trans retinoic acid (ATRA) suppresses transcription of human papillomavirus type 16 (HPV16) in a dose-dependent manner. Anticancer Res 2004, 24, 807–809.
Feart C, Vallortigara J, Hiqueret D, Gatta B, Tabarin A, Enderlin V, Hiqueret P, Pallet V: Decreased expression of retinoid nuclear receptor (RARalpha and RARgamma) mRNA determined by real-time quantitative RT-PCR in peripheral blood mononuclear cells of hyperthyroid patients. J Mol Endocrin 2005, 34, 849–858.
Ferrucci PF, Grignani F, Pearson M, Fagioli M, Nicoletti I, Pellici PG: Cell death induction by the acute promyelocytic leukemia-specific PML/RAR alpha fusion protein. Proc Nat Acad Sci USA 1997, 94, 10901–10906.
Fields AL, Soprano DR, Soprano KJ: Retinoids in biological control and cancer. J Cell Biochem 2007, 102, 886–898.
Freemantle SJ, Spinella MJ, Dmitrovsky E: Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 2003, 22, 7305–7315.
Geisen C, Denk C, Kupper JH, Schwarz E: Growth inhibition of cervical cancer cells by the human retinoic acid receptor beta gene. Int J Cancer 2000, 85, 289–295.
Gerster H: Vitamin A functions, dietary, requirements and safety in human. Int J Vitam Nutr Res 1997, 67, 71–90.
Hansen LA, Sigman CC, Andreda F, Ross SA, Kelloff GJ, De Luca LM: Retinoids in chemoprevention and differentiation therapy. Carcinogenesis 2000, 21, 1271–1279.
Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, Schantz SP, Kramer AM, Lotan R, Peters LJ, Dimery IW, Brown BW, Goepfert G: Prevention of secondary primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990, 323, 795–801.
Hoppe-Seyler F, Butz K: Cellular control of human papillomavirus oncogene transcription. Mol Carcinog 1994, 10, 134–141.
Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WI, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z: Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2009, 106, 3342–3347.
Hurnanen D, Chan M, Kubow S: The protective effect of matallothionein ahainst lipid peroxidation caused by retinoic acid in human breast cancer cells. J Pharmacol Exp Ther 1997, 283, 1520–1528.
Leid M, Kastner P, Chambon P: Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 1999, 10, 427–433.
Lintig J, Vogt K: Vitamin A formation in animals: molecular identification and functional characterization of carotene cleaving enzymes. J Nutr 2004, 143, 251S–256S.
Liu S, Wu S, Chen ZM, Su WJ: The effect pathway of retinoic acid through regulation of retinoic acid receptor alfa in gastric cancer cells. World J Gastroenterol 2001, 5, 662–666.
Moasser MM, Khoo KS, Maerz WJ, Zelenetz A, Dmitrowsky E: Derivation and characterization of retinoid-resistant human embryonal carcinoma cells. Differentiation 1996, 4, 251–257.
Okono M, Kojima S, Matsishima-Ishiwaki R, Tsurumi H, Muto Y, Friedman SL, Moriwaki H: Retinoids in cancer chemoprevention. Curr Cancer Drug Targets 2004, 4, 285–298.
Sano K, Takayama T, Murakami K, Saiki I, Makuuchi M: Overexpression of retinoic acid receptor alpha in hepatocellular carcinoma. Clinical Cancer Res 2003, 9, 3679–3683.
Shaulian E, Karin M: AP-1 as a regulator of cell life and death. Nat Cell Biol 2002, 4, E131–E136.
Somenzi G, Sala G, Rossetti S, Ren MQ, Ghidoni R, Sacchi N: Disruption of retinoic acid receptor alpha reveals the growth promoter face of retinoic acid. PLoS One 2007, 9, e836, doi.1371/journal.pone 0000836.
Soprano DR, Soprano KJ: Pharmacological doses of some synthetic retinoids can modulate both the aryl hydrocarbon receptor and retinoid receptor pathways. J Nutr 2003, 24, 277S–281S.
Sun SY, Lotan R: Retinoids and their receptors in cancer development and chemoprevention. Crit Rev Oncol Hematol 2002, 41, 41–55.
Swift ME, Wallden B, Wayner EA, Swisshelm T: Truncated RAR beta isoform enhances proliferation and retinoid resistance. J Cell Physiol 2006, 209, 718–725.
Tang XH, Gudas LJ: Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol 2011, 6, 345–364.
van der Leede BM, Geertzema J, Vroom TM, Decimo D, Lutz Y, van der Saaq PT, van der Burq B: Immunohistochemical analysis of retinoic acid receptor-alpha in human breast tumors: retinoic acid receptor alpha explosion correlates with proliferative activity. Am J Pathol 1994, 6, 1905–1914.
Warrel RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 1991, 324, 1385–1393.
Xu XC, Mitchell MF, Sitra E, Jetten A, Lotan R: Decreased expression of retinoic acid receptors, transforming growth factor beta, involucrin, and cornifin in cervical intraepithelial neoplasia. Clin Cancer Res 1999, 6, 1500–1508.
Zeng M, Kumar A, Meng G, Gao Q, Dimri G, Wazer D, Band H, Band V: Human papilloma virus 16 E6 oncoprotein inhibits retinoic Xreceptor-mediated transactivation by targeting human ADA3 coactivator. J Biol Chem 2007, 277, 45611–45618.
Zhou XF, Shen XQ, Shemshedini L: Ligand-activated retinoic acid receptor inhibits AP-1 transactivation by disrupting c-Jun/c-Fos dimerization. Mol Endocrinol 1999, 13, 276–285.
zur Hausen H: Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002, 2, 342–350.