Vitamin D and its Role in Cell Cycle Dynamics: A Review of the Molecular and Clinical Studies

Irawan Sastradinata; Krisna  Murti; Irsan  Saleh; Tatit  Nurseta

doi:10.37899/journallamedihealtico.v6i3.2096

Irawan Sastradinata Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Sriwijaya University/Dr. Mohammad Hoesin General Hospital, Palembang
Krisna Murti Department of Anatomic Pathology, Dr. Mohammad Hoesin General Hospital/Faculty of Medicine, Sriwijaya University, Palembang
Irsan Saleh Department of Pharmacology, Faculty of Medicine, Sriwijaya University, Palembang
Tatit Nurseta Division of Gynecologic Oncology, Department of Obstetrics and Gyencology, Brawijaya University Malang

DOI: https://doi.org/10.37899/journallamedihealtico.v6i3.2096

Keywords: Vitamin D, Cell Cycle, Oncogenesis

Abstract

Vitamin D is an essential nutrient that not only plays a role in calcium homeostasis and bone health, but also has broad functions in the regulation of various biological processes, including cell cycle dynamics. This study aims to examine in depth the role of vitamin D in cell cycle dynamics based on evidence from molecular and clinical studies. The method used was qualitative research with a literature study approach, where data was collected from relevant articles such as PubMed, EuropePMC, and Google Scholar. Analysis was carried out through the process of filtering, presenting data, and drawing conclusions. The results showed that vitamin D in its active form, 1,25-dihydroxyvitamin D3, interacts with the vitamin D receptor (VDR) in cells and modulates the expression of genes involved in cell proliferation. This mechanism involves an increase in the expression of cell cycle inhibitory genes, such as p21 and p27, and a decrease in the expression of cell cycle promoting genes, such as cyclin D1, which contributes to the arrest effect on the cell cycle. Thus, in addition to being important for bone health, vitamin D has a significant role in cell cycle regulation, and its deficiency can increase the risk of various diseases, including cancer. Therefore, maintaining optimal vitamin D levels through sun exposure, consumption of foods rich in vitamin D, or supplementation is essential. Further research is needed to understand the role of vitamin D in genetic regulation, particularly in relation to cancer.

References

Artaza, J. N., Sirad, F., Ferrini, M. G., & Norris, K. C. (2010). 1, 25 (OH) 2vitamin D3 inhibits cell proliferation by promoting cell cycle arrest without inducing apoptosis and modifies cell morphology of mesenchymal multipotent cells. The Journal of steroid biochemistry and molecular biology, 119(1-2), 73-83. https://doi.org/10.1016/j.jsbmb.2010.01.001

Bao, A., Li, Y., Tong, Y., Zheng, H., Wu, W., & Wei, C. (2014). 1, 25-Dihydroxyvitamin D3 and cisplatin synergistically induce apoptosis and cell cycle arrest in gastric cancer cells. International journal of molecular medicine, 33(5), 1177-1184. https://doi.org/10.3892/ijmm.2014.1664

Bhoora, S., & Punchoo, R. (2020). Policing cancer: vitamin D arrests the cell cycle. International journal of molecular sciences, 21(23), 9296. https://doi.org/10.3390/ijms21239296

Bikle, D. D. (2004). Vitamin D regulated keratinocyte differentiation. Journal of cellular biochemistry, 92(3), 436-444. https://doi.org/10.1002/jcb.20095

Bikle, D. D. (2014). Vitamin D metabolism, mechanism of action, and clinical applications. Chemistry & biology, 21(3), 319-329.

Christakos, S., Dhawan, P., Verstuyf, A., Verlinden, L., & Carmeliet, G. (2016). Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiological reviews, 96(1), 365-408. https://doi.org/10.1152/physrev.00014.2015

Contreras-Bolívar, V., García-Fontana, B., García-Fontana, C., & Muñoz-Torres, M. (2021). Mechanisms involved in the relationship between vitamin D and insulin resistance: impact on clinical practice. Nutrients, 13(10), 3491. https://doi.org/10.3390/nu13103491

Ding, L., Cao, J., Lin, W., Chen, H., Xiong, X., Ao, H., ... & Cui, Q. (2020). The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. International journal of molecular sciences, 21(6), 1960. https://doi.org/10.3390/ijms21061960

El-Sharkawy, A., & Malki, A. (2020). Vitamin D signaling in inflammation and cancer: molecular mechanisms and therapeutic implications. Molecules, 25(14), 3219. https://doi.org/10.3390/molecules25143219

Engeland, K. (2018). Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death & Differentiation, 25(1), 114-132. https://doi.org/10.1038/cdd.2017.172

Gérard, C., & Goldbeter, A. (2014). The balance between cell cycle arrest and cell proliferation: control by the extracellular matrix and by contact inhibition. Interface focus, 4(3), 20130075. https://doi.org/10.1098/rsfs.2013.0075

Goel, S., DeCristo, M. J., McAllister, S. S., & Zhao, J. J. (2018). CDK4/6 inhibition in cancer: beyond cell cycle arrest. Trends in cell biology, 28(11), 911-925.

Hu, X. T., & Zuckerman, K. S. (2014). Role of cell cycle regulatory molecules in retinoic acid‐and vitamin D3‐induced differentiation of acute myeloid leukaemia cells. Cell Proliferation, 47(3), 200-210. https://doi.org/10.1111/cpr.12100

Hydbring, P., Malumbres, M., & Sicinski, P. (2016). Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nature reviews Molecular cell biology, 17(5), 280-292. https://doi.org/10.1038/nrm.2016.27

Irazoqui, A. P., Heim, N. B., Boland, R. L., & Buitrago, C. G. (2015). 1α, 25 dihydroxi-vitamin D3 modulates CDK4 and CDK6 expression and localization. Biochemical and Biophysical Research Communications, 459(1), 137-142. https://doi.org/10.1016/j.bbrc.2015.02.083

Jeon, S. M., & Shin, E. A. (2018). Exploring vitamin D metabolism and function in cancer. Experimental & molecular medicine, 50(4), 1-14. https://doi.org/10.1038/s12276-018-0038-9

Jones, M. C., Zha, J., & Humphries, M. J. (2019). Connections between the cell cycle, cell adhesion and the cytoskeleton. Philosophical Transactions of the Royal Society B, 374(1779), 20180227. https://doi.org/10.1098/rstb.2018.0227

Karimian, A., Ahmadi, Y., & Yousefi, B. (2016). Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA repair, 42, 63-71. https://doi.org/10.1016/j.dnarep.2016.04.008

Kumar, V., Abbas, A. K., Aster, J. C., & Deyrup, A. T. (Eds.). (2022). Robbins & Kumar basic pathology, e-book: Robbins & Kumar basic pathology, e-book. Canada: Elsevier Health Sciences.

Kumari, R., & Jat, P. (2021). Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Frontiers in cell and developmental biology, 9, 645593. https://doi.org/10.3389/fcell.2021.645593

Li, H. X., Gao, J. M., Liang, J. Q., Xi, J. M., Fu, M., & Wu, Y. J. (2015). Vitamin D3 potentiates the growth inhibitory effects of metformin in DU 145 human prostate cancer cells mediated by AMPK/mTOR signalling pathway. Clinical and Experimental Pharmacology and Physiology, 42(6), 711-717. https://doi.org/10.1111/1440-1681.12409

Li, M., Li, L., Zhang, L., Hu, W., Shen, J., Xiao, Z., ... & Cho, C. H. (2017). 1, 25-Dihydroxyvitamin D3 suppresses gastric cancer cell growth through VDR-and mutant p53-mediated induction of p21. Life Sciences, 179, 88-97. https://doi.org/10.1016/j.lfs.2017.04.021

Lim, S., & Kaldis, P. (2013). Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development, 140(15), 3079-3093. https://doi.org/10.1242/dev.091744

Martínez-Alonso, D., & Malumbres, M. (2020, November). Mammalian cell cycle cyclins. In Seminars in cell & developmental biology (Vol. 107, pp. 28-35). Academic Press. https://doi.org/10.1016/j.semcdb.2020.03.009

Pickholtz, I., Saadyan, S., Keshet, G. I., Wang, V. S., Cohen, R., Bouwman, P., ... & Yarden, R. I. (2014). Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and for growth inhibition of breast cancer cells and cancer stem-like cells. Oncotarget, 5(23), 11827. https://doi.org/10.18632/oncotarget.2582

Pike, J. W., Meyer, M. B., Benkusky, N. A., Lee, S. M., John, H. S., Carlson, A., ... & Shamsuzzaman, S. (2016). Genomic determinants of vitamin D-regulated gene expression. Vitamins & hormones, 100, 21-44. https://doi.org/10.1016/bs.vh.2015.10.011

Pilon, C., Urbanet, R., Williams, T. A., Maekawa, T., Vettore, S., Sirianni, R., ... & Fallo, F. (2014). 1α, 25-Dihydroxyvitamin D3 inhibits the human H295R cell proliferation by cell cycle arrest: a model for a protective role of vitamin D receptor against adrenocortical cancer. The Journal of Steroid Biochemistry and Molecular Biology, 140, 26-33. https://doi.org/10.1016/j.jsbmb.2013.11.008

Ruijtenberg, S., & van den Heuvel, S. (2016). Coordinating cell proliferation and differentiation: Antagonism between cell cycle regulators and cell type-specific gene expression. Cell cycle, 15(2), 196-212. https://doi.org/10.1080/15384101.2015.1120925

Saponaro, F., Saba, A., & Zucchi, R. (2020). An update on vitamin D metabolism. International journal of molecular sciences, 21(18), 6573. https://doi.org/10.3390/ijms21186573

Slominski, A. T., Brożyna, A. A., Zmijewski, M. A., Jóźwicki, W., Jetten, A. M., Mason, R. S., ... & Elmets, C. A. (2017). Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management. Laboratory Investigation, 97(6), 706-724. https://doi.org/10.1038/labinvest.2017.3

Umar, M., Sastry, K. S., & Chouchane, A. I. (2018). Role of vitamin D beyond the skeletal function: a review of the molecular and clinical studies. International journal of molecular sciences, 19(6), 1618. https://doi.org/10.3390/ijms19061618

Zou, T., & Lin, Z. (2021). The involvement of ubiquitination machinery in cell cycle regulation and cancer progression. International Journal of Molecular Sciences, 22(11), 5754. https://doi.org/10.3390/ijms22115754