Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press117810.17650/1726-9784-2019-18-4-43-50REVIEWSОБЗОРЫ ЛИТЕРАТУРЫNON-CANONICAL ACTIVITY OF RETINOIC ACID AS A POSSIBLE MECHANISM OF RETINOID RESISTANCE IN CANCER THERAPYНЕКАНОНИЧЕСКАЯ АКТИВНОСТЬ РЕТИНОЕВОЙ КИСЛОТЫ КАК ВОЗМОЖНЫЙ МЕХАНИЗМ ФОРМИРОВАНИЯ РЕЗИСТЕНТНОСТИ ЗЛОКАЧЕСТВЕННЫХ КЛЕТОК К РЕТИНОИДНОЙ ТЕРАПИИhttps://orcid.org/0000-0002-7628-8616EnikeevA. D.ЕникеевА. Д.
Russian Federation

24 Kashirskoye Shosse, Moscow 115478, Russia

Россия, 115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0003-0766-163XKomelkovA. V.КомельковА. В.
Russian Federation

24 Kashirskoye Shosse, Moscow 115478, Russia

Россия, 115478 Москва, Каширское шоссе, 24

komelkov@gmail.comhttps://orcid.org/0000-0003-2778-7870AkselrodM. E.АксельродМ. Е.
Russian Federation

24 Kashirskoye Shosse, Moscow 115478, Russia

Россия, 115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0001-8837-7969TchevkinaE. M.ЧевкинаЕ. М.
Russian Federation

24 Kashirskoye Shosse, Moscow 115478, Russia

Россия, 115478 Москва, Каширское шоссе, 24

N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Hearth of the Russian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России0212201918443503011201930112019https://bioterapevt.abvpress.ru/jour/article/view/1178

Retinoic acid (RA) is one of the most functionally active intracellular metabolites of vitamin A, regulating the key physiological processes, including the differentiation of cells, organs and tissues. RA is successfully applied in the treatment of acute promyelocytic leukemia. Drugs based on RA and other natural and synthetic retinoids are being actively developed for the treatment of other oncopathologies, including various solid tumors. However, the use of RA in the treatment of malignant tumors is restricted by the rapid acquisition of RA-resistance. The mechanisms of RA-resistance formation are still poorly understood, what could be explained apparently by the large number of genes directly or indirectly being regulated by RA at transcription level, including genes regulating the activity and metabolism of RA itself. The situation is further complicated by the relatively recently discovered non-genomic or non-canonical activity of RA, which consists in the non-transcriptional regulation of key protein kinases involved in tumor progression. The review is devoted to the analysis of published data on non-canonical activity of RA. The review provides a modern view on the main mechanisms implementing the canonical genomic activity of the RA, presents available information on the RA-dependent non-transcriptional regulation of ERK1 / 2, PI3K / AKT, p38MAPK and PKC protein kinases and possible mechanisms mediating this activity as well as potential significance of the RA-dependent activation of intracellular signaling pathways in the formation of RA-resistance and the malignant potential of transformed cells.

Ретиноевая кислота (РК) является одним из наиболее функционально значимых внутриклеточных метаболитов витамина А, регулирующим важнейшие физиологические процессы, включая дифференцировку клеток, органов и тканей. РК успешно применяется в терапии острого промиелоцитарного лейкоза. Препараты на основе РК и других природных и синтетических ретиноидов активно разрабатываются для лечения и других онкопатологий, включая различные солидные опухоли. Однако применение РК в терапии злокачественных опухолей сильно ограничено быстрым приобретением клетками РК-резистентности. Механизмы формирования устойчивости к РК до сих пор малопонятны, что объясняется, по‑видимому, большим количеством генов, транскрипция которых прямо или опосредованно регулируется РК, в том числе генов, регулирующих активность и метаболизм самой РК. Ситуация дополнительно усложняется сравнительно недавно обнаруженной негеномной, или неканонической, активностью РК, которая заключается в нетранскрипционной регуляции ключевых протеинкиназ, задействованных в опухолевой прогрессии. Обзор посвящен анализу данных литературы о неканонической активности РК. В нем изложены современные представления об основных механизмах, реализующих каноническую геномную активность РК, представлены имеющиеся на сегодняшний день сведения об РК-зависимой нетранскрипционной регуляции протеинкиназ ERK1 / 2, PI3K / AKT, p38MAPK и PKC, рассмотрены возможные механизмы, реализующие данную активность РК, а также значение РК-зависимой активации внутриклеточных сигнальных путей в формированиии РК-резистентности и изменении злокачественного потенциала малигнизированных клеток.

Retinoic acidnon-canonical activitynuclear receptorsprotein kinaseRA-resistanceретиноевая кислотанеканоническая активностьядерные рецепторыпротеинкиназаРК-резистентностьThe study was performed with the support of Russian Foundation for Basic Research, project No 19-015-00027 А.Исследование проведено при поддержке Российского Фонда фундаментальных исследований, проект № 19-015-00027 А.Di Masi A., Leboffe L., de Marinis E. et al. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol Aspects Med 2015;41:1–115. DOI: 10.1016/j.mam.2014.12.003.Chen M.-C., Hsu S.-L., Lin H., Yang T.-Y. Retinoic acid and cancer treatment. Biomedicine (Taipei) 2014;4(4):22–2. DOI: 10.7603/s40681-014-0022-1.Connolly R.M., Nguyen N.K., Sukumar S. Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment. Clin Cancer Res 2013;19(7):1651–9. DOI: 10.1158/1078-0432.CCR-12-3175.Chlapek P., Slavikova V., Mazanek P. et al. Why differentiation therapy sometimes fails: molecular mechanisms of resistance to retinoids. Int J Mol Sci 2018;19(1): 132. DOI: 10.3390/ijms19010132Ross-Innes C.S., Stark R., Holmes K.А. et al. Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer. Genes Dev 2010;24(2):171–82. DOI: 10.1101/gad.552910.Al Tanoury Z., Piskunov A., Rochette-Egly C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J Lipid Res 2013;54(7):1761–75. DOI: 10.1194/jlr.R030833.Mrass P., Rendl M., Mildner M. et al. Retinoic acid increases the expression of p53 and proapoptotic caspases and sensitizes keratinocytes to apoptosis. Cancer Res 2004;64(18):6542–8. DOI: 10.1158/0008-5472.CAN-04-1129.Zhang H., Rosdahl I. Expression profiles of p53, p21, bax and bcl-2 proteins in alltrans-retinoic acid treated primary and metastatic melanoma cells. Int J Oncol 2004;25(2):303–8.Luscher B., Mitchell P.J., Williams T., Tjian R. Regulation of transcription factor AP-2 by the morphogen retinoic acid and by second messengers. Genes Dev 1989;3(10):1507–17. DOI: 10.1101/gad.3.10.1507.Donato L.J., Suh J.H., Noy N. Suppression of mammary carcinoma cell growth by retinoic acid: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling. Cancer Res 2007;67(2):609–15. DOI: 10.1158/0008-5472.CAN-06-0989.Donato L.J., Noy N. Suppression of mammary carcinoma growth by retinoic acid: proapoptotic genes are targets for retinoic acid receptor and cellular retinoic acid-binding protein II signaling. Cancer Res 2005;65(18):8193–9. DOI: 10.1158/0008-5472.CAN-05-1177.Raffo P., Emionite L., Colucci L. et al. Retinoid receptors: pathways of proliferation inhibition and apoptosis induction in breast cancer cell lines. Anticancer Res 2000;20(3a):1535–43.Raffo P., Emionite L., Colucci L. et al. Retinoid receptors: pathways of proliferation inhibition and apoptosis induction in breast cancer cell lines. Anticancer Res 2000;20(3a):1535–43.Altucci L., Rossin A., Raffelsberger W. et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 2001;7(6):680–6. DOI: 10.1038/89050.Kitareewan S., Pitha-Rowe I., Sekula D. et al. UBE1L is a retinoid target that triggers PML/RARα degradation and apoptosis in acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2002;99(6):3806–11. DOI: 10.1073/pnas.052011299.Park D.J., Chumakov A.M., Vuong P.T. et al. CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment. J Clin Invest 1999;103(10):1399–408. DOI: 10.1172/JCI2887.Afonja O., Juste D., Das S. et al. Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis. Oncogene 2004;23(49): 8135–45. DOI: 10.1038/sj.onc.1207983.Afonja O., Raaka B.M., Huang A. et al. RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition. Oncogene 2002;21(51):7850–60. DOI: 10.1038/sj.onc.1205985.De Thè H., Vivanco-Ruiz M.М., Tiollais P. et al. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 1990;343(6254):177–80. DOI: 10.1038/343177a0.Liu Y., Lee M.O., Wang H.G. et al. Retinoic acid receptor beta mediates the growth-inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells. Mol Cell Biol 1996;16(3):1138–49. DOI: 10.1128/MCB.16.3.1138.Sirchia S.M., Ren M., Pili R. et al. Endogenous reactivation of the RARbeta2 tumor suppressor gene epigenetically silenced in breast cancer. Cancer Res 2002;62(9):2455–61.Sirchia S.M., Ren M., Pili R. et al. Endogenous reactivation of the RARbeta2 tumor suppressor gene epigenetically silenced in breast cancer. Cancer Res 2002;62(9):2455–61.Tchevkina E.M. Retinoic Acid Binding Proteins and Cancer: Similarity or Polarity? Cancer Therapy & Oncology Int J 2017;8(2):555733. DOI: 10.19080/ctoij.2017.08.555733.Tchevkina E.M., Favorskaya I.A. CRABP proteins – relatives or homonyms? Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2015;2(2):6–16. (In Russ.)Чевкина Е.М., Фаворская И.А. Белки CRABP – родственники или однофамильцы? Успехи молекулярной онкологии 2015;2(2):6–16.Noy N. Non-classical transcriptional activity of retinoic acid. Subcell Biochem 2016;81:179–99. DOI: 10.1007/978-94-024-0945-1_7.García-Regalado A., Vargas M., García-Carrancá A. et al. Activation of Akt pathway by transcriptionindependent mechanisms of retinoic acid promotes survival and invasion in lung cancer cells. Mol Cancer 2013;12:44. DOI: 10.1186/1476-4598-12-44.López-Carballo G., Moreno L., Masiá S. et al. Activation of the phosphatidylinositol 3-kinase/akt signaling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells. J Biol Chem 2002;277(28):25297– 304. DOI: 10.1074/jbc.m201869200.Masiá S., Alvarez S., de Lera A.R., Barettino D. Rapid, nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor. Mol Endocrinol 2007;21(10):2391–402. DOI: 10.1210/me.2007-0062.Persaud S.D., Lin Y.-W., Wu C.-Y. et al. Cellular retinoic acid binding protein I mediates rapid non-canonical activation of ERK1/2 by all-trans retinoic acid. Cell Signal 2013;25(1):19–25. DOI: 10.1016/j.cellsig.2012.09.002.Persaud S.D., Park S.W., Ishigami-Yuasa M. et al. Erratum: Corrigendum: All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation. Sci Rep 2016; 6(1):27678. DOI: 10.1038/srep27678.Enikeev A.D., Komelkov A.V., Zborovskaya I.B. et al. Non-canonical activity of retinoic acid in relation to the activation of protein kinases in transformed cells of different origin. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2018;5(4):127–30. (In Russ.) DOI: 10.17650/2313-805X-2018-5-4-127-130.Еникеев А.Д., Комельков А.В., Зборовская И.Б. и др. Неканоническая активность ретиноевой кислоты в отношении активации протеинкиназ в трансформированных клетках различного происхождения. Успехи молекулярной онкологии 2018; 5(4):127–30. DOI: 10.17650/2313-805X-2018-5-4-127-130.Quintero Barceinas R.S., García-Regalado A., Aréchaga-Ocampo E. et al. All-Trans Retinoic Acid Induces Proliferation, Survival, and Migration in A549 Lung Cancer Cells by Activating the ERK Signaling Pathway through a Transcription-Independent Mechanism. Biomed Res Int 2015;2015:404368. DOI: 10.1155/2015/404368.Giannì M., Parrella E., Raska I. et al. P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARα-mediated transcription. EMBO J 2006;25(4):739–51. DOI: 10.1038/sj.emboj.7600981.Bruck N., Vitoux D., Ferry C. et al. A coordinated phosphorylation cascade initiated by MSK1 directs RAR alpha recruitment to target gene promoters. Nature Precedings 2008. DOI: 10.1038/npre.2008.2107.1.Piskunov A., Rochette-Egly C. A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK. Oncogene 2011;31(28):3333–45. DOI: 10.1038/onc.2011.499.Alsayed Y., Uddin S., Mahmud N. et al. Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to all-trans-retinoic acid. J Biol Chem 2000;276(6):4012–9. DOI: 10.1074/jbc.m007431200.Ochoa W.F.,Torrecillas A., Fita I. et al. Retinoic Acid Binds to the C2-Domain of Protein Kinase Cα†. Biochemistry 2003;42(29):8774–9. DOI: 10.1021/bi034713g.Radominska-Pandya A., Chen G., Czernik P.J. et al. Direct interaction of all-trans-retinoic acid with protein kinase C (PKC). J Biol Chem 2000;275(29): 22324–30. DOI: 10.1074/jbc.m907722199.