Effects of vitamin D on proliferation, invasion and energy metabolism of MCF-7 breast cancer cell line

Background and Aims: 1,25(OH)2D3 (vitamin D) is a pleiotropic hormone with anti-proliferative, pro-apoptotic, and pro- differentiation effects on various cell types, which suggest anti-cancer activity in addition to its classical regulatory action on calcium and phosphate metabolism.Methods: We aimed to put forward the effects of vitamin D in various concentrations and time intervals on cell proliferation and invasion of human estrogen receptor-positive breast cancer (MCF-7) cells by real-time cell electronic sensing system (xCELLigence). A determined dose of the IC50 was applied on samples taken from cell lysates and analyzed the levels of the energy. We also aimed to clarify how vitamin D effects the activity of the protease uPA and their relations with each other.Results: Vitamin D showed a cytotoxic effect on MCF-7 cells in a time and dose dependent manner, with dose of IC50 found to be 140 nM. ATP, ADP, and AMP levels, as well as uPA activities were respectively increased in vitamin D treatment group compared to the control group for the first 24 hours while decreasing at 48, 72, and 96 hours. We determined that 70 and 140 nM vitamin D were decreased in invasion of MCF-7 cells compared to control cells.Conclusion: We observed that proliferation and invasion of breast cancer cells were inhibited by vitamin D treatment on a dose and time dependent manner, and also vitamin D supplementation decreased uPA activity and energy levels. Further studies on the mechanisms of vitamin D and the formulation of none-hypercalcemic analogues in featured are needed.

Keywords:

Activity of uPA, Energy levels, Invasion Proliferation, Vitamin D,

PDF

___

Abbas, S., Chang‐Claude, J., & Linseisen, J. (2009). Plasma 25‐hy- droxyvitamin D and premenopausal breast cancer risk in a Ger- man case‐control study. International journal of cancer, 124(1), 250-255.
Anderson, P. H. (2017). Vitamin D Activity and Metabolism in Bone. Current Osteoporosis Reports, 15(5), 443-449. doi:10.1007/ s11914-017-0394-8
Brosseau, C., Pirianov, G., & Colston, K. (2010). Involvement of stress activated protein kinases (JNK and p38) in 1, 25 dihydroxyvitamin D3-induced breast cell death. Steroids, 75(13-14), 1082-1088.
Chiang, K. C., Chen, S. C., Yeh, C. N., Pang, J. H., Shen, S. C., Hsu, J. T., Chen, T. C. (2014). MART-10, a less calcemic vitamin D analog, is more potent than 1alpha,25-dihydroxyvitamin D3 in inhibit- ing the metastatic potential of MCF-7 breast cancer cells in vitro. Journal of Steroid Biochemistry and Molecular Biology, 139, 54-60. doi:10.1016/j.jsbmb.2013.10.005
Cimen, B., Turkozkan, N., Unlu, A., & Erbil, M. K. (2005). Effects of melatonin on 3-nitrotyrosine formation and energy charge ratio in guinea pig kidney in LPS-induced stress. Cell Biochemistry and Function, 23(4), 273-277. doi:10.1002/cbf.1151
Diesing, D., Cordes, T., Fischer, D., Diedrich, K., & Friedrich, M. (2006). Vitamin D--metabolism in the human breast cancer cell line MCF-7. Anticancer Research, 26(4A), 2755-2759.
Dinicola, S., Pasqualato, A., Cucina, A., Coluccia, P., Ferranti, F., Cani- pari, R., . . . Bizzarri, M. (2014). Grape seed extract suppresses MDA- MB231 breast cancer cell migration and invasion. European Jour- nal of Nutrition, 53(2), 421-431. doi:10.1007/s00394-013-0542-6
Duffy, M. J., & Duggan, C. (2004). The urokinase plasminogen ac- tivator system: a rich source of tumour markers for the individu- alised management of patients with cancer. Clinical Biochemistry, 37(7), 541-548. doi:10.1016/j.clinbiochem.2004.05.013
Fehm, T., Zwirner, M., Wallwiener, D., Seeger, H., & Neubauer, H. (2012). Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity as- say. BMC Cancer, 12, 308. doi:10.1186/1471-2407-12-308
Flanagan, L., Packman, K., Juba, B., O’Neill, S., Tenniswood, M., & Welsh, J. (2003). Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion. Journal of Steroid Biochemistry and Molecular Biology, 84(2-3), 181- 192.
Friedrich, M., Diesing, D., Cordes, T., Fischer, D., Becker, S., Chen, T. C., . . . Reichrath, J. (2006). Analysis of 25-hydroxyvitamin D3- 1alpha-hydroxylase in normal and malignant breast tissue. Anti- cancer Research, 26(4A), 2615-2620.
Garland, C., Garland, F., Gorham, E., & Raffa, J. (1991). Sunlight, vi- tamin D, and mortality from breast and colorectal cancer in Italy. Biologie Effects of Light, 39.
Garland, C. F., Garland, F. C., Gorham, E. D., Lipkin, M., Newmark, H., Mohr, S. B., & Holick, M. F. (2006). The role of vitamin D in cancer prevention. American journal of public health, 96(2), 252-261.
Kamińska, M., Ciszewski, T., Łopacka-Szatan, K., Miotła, P., & Starosławska, E. (2015). Breast cancer risk factors. Przeglad meno- pauzalny= Menopause review, 14(3), 196.
Kaur, G., Behrsing, H., Parchment, R. E., Millin, M. D., & Teicher, B. A. (2013). Analyses of the combination of 6-MP and dasatinib in cell culture. International Journal of Oncology, 43(1), 13-22. doi:10.3892/ijo.2013.1930
Kim, H. A., Kim, M. S., Kim, S. H., & Kim, Y. K. (2014). Pepper seed ex- tract suppresses invasion and migration of human breast cancer cells. Nutrition and Cancer, 66(1), 159-165. doi:10.1080/01635581. 2014.853814
Lim, H. S., Roychoudhuri, R., Peto, J., Schwartz, G., Baade, P., & Moller, H. (2006). Cancer survival is dependent on season of di- agnosis and sunlight exposure. International Journal of Cancer, 119(7), 1530-1536. doi:10.1002/ijc.22052
Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193(1), 265-275.
Marchionatti, A. M., Picotto, G., Narvaez, C. J., Welsh, J., & Tolosa de Talamoni, N. G. (2009). Antiproliferative action of menadione and 1,25(OH)2D3 on breast cancer cells. Journal of Steroid Bio- chemistry and Molecular Biology, 113(3-5), 227-232. doi:10.1016/j. jsbmb.2009.01.004
Mathiasen, I. S., Lademann, U., & Jäättelä, M. (1999). Apoptosis in- duced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. Cancer re- search, 59(19), 4848-4856.
Meijer-van Gelder, M. E., Look, M. P., Peters, H. A., Schmitt, M., Brünner, N., Harbeck, N., . . . Foekens, J. A. (2004). Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease. Cancer Research, 64(13), 4563-4568.
Ning, Y. L., Qi, C. J., Lu, X. Z., Zhu, Y. L., Qian, K. Q., & Zhao, J. Z. (2011). The predictive value of epidermal growth factor receptor expres- sion for sensitivity to vinorelbine in breast cancer. Basic & Clinical Pharmacology & Toxicology, 109(6), 499-505. doi:10.1111/j.1742- 7843.2011.00759.x
Ooi, L. L., Zheng, Y., Zhou, H., Trivedi, T., Conigrave, A. D., Seibel, M. J., & Dunstan, C. R. (2010). Vitamin D deficiency promotes growth of MCF-7 human breast cancer in a rodent model of os- teosclerotic bone metastasis. Bone, 47(4), 795-803. doi:10.1016/j. bone.2010.07.012
Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell metabolism, 23(1), 27-47.
Porojnicu, A. C., Lagunova, Z., Robsahm, T. E., Berg, J. P., Dahlback, A., & Moan, J. (2007). Changes in risk of death from breast cancer with season and latitude: sun exposure and breast cancer survival in Norway. Breast Cancer Research and Treatment, 102(3), 323-328. doi:10.1007/s10549-006-9331-8
Proietti, S., Cucina, A., D’Anselmi, F., Dinicola, S., Pasqualato, A., Lisi, E., & Bizzarri, M. (2011). Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFbeta-1-dependent growth inhibition of breast cancer cells. Journal of Pineal Research, 50(2), 150-158. doi:10.1111/j.1600-079X.2010.00824.x
Robsahm, T. E., Tretli, S., Dahlback, A., & Moan, J. (2004). Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control, 15(2), 149-158. doi:10.1023/b:caco.0000019494.34403.09
Rossi, M., McLaughlin, J. K., Lagiou, P., Bosetti, C., Talamini, R., Lip- worth, L., . . . La Vecchia, C. (2009). Vitamin D intake and breast cancer risk: a case-control study in Italy. Annals of Oncology, 20(2), 374-378. doi:10.1093/annonc/mdn550
Schmitt, M., Harbeck, N., Thomssen, C., Wilhelm, O., Magdolen, V., Reuning, U., . . . Graeff, H. (1997). Clinical impact of the plasmino- gen activation system in tumor invasion and metastasis: prog- nostic relevance and target for therapy. Thrombosis and haemo- stasis, 78(01), 285-296.
Sliva, D. (2004). Signaling pathways responsible for cancer cell in- vasion as targets for cancer therapy. Current Cancer Drug Targets, 4(4), 327-336.
So, J. Y., Smolarek, A. K., Salerno, D. M., Maehr, H., Uskokovic, M., Liu, F., & Suh, N. (2013). Targeting CD44-STAT3 signaling by Gemini vi- tamin D analog leads to inhibition of invasion in basal-like breast cancer. PLoS One, 8(1), e54020. doi:10.1371/journal.pone.0054020
Sucha, L., Hroch, M., Rezacova, M., Rudolf, E., Havelek, R., Sispera, L., . . . Tomsik, P. (2013). The cytotoxic effect of alpha-tomatine in MCF-7 human adenocarcinoma breast cancer cells depends on its interaction with cholesterol in incubation media and does not involve apoptosis induction. Oncology Reports, 30(6), 2593-2602. doi:10.3892/or.2013.2778
Sundaram, S., Beckman, M. J., Bajwa, A., Wei, J., Smith, K. M., Posner, G. H., & Gewirtz, D. A. (2006). QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells. Molecular Cancer Therapeutics, 5(11), 2806- 2814. doi:10.1158/1535-7163.mct-06-0092
Uitterlinden, A. G., Fang, Y., Van Meurs, J. B., Pols, H. A., & Van Leeu- wen, J. P. (2004). Genetics and biology of vitamin D receptor poly- morphisms. Gene, 338(2), 143-156. doi:10.1016/j.gene.2004.05.014
Veldhuis, S., Wolbers, F., Brouckaert, O., Vermes, I., & Franke, H. R. (2011). Cancer prevalence in osteoporotic women with low se- rum vitamin D levels. Menopause, 18(3), 319-322. doi:10.1097/ gme.0b013e3181f81ad5
Welsh, J. (2021). Vitamin D and Breast Cancer: Mechanistic Up- date. JBMR plus, 5(12), e10582.
Wietzke, J. A., & Welsh, J. (2003). Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 ac- tions in human breast cancer cells. Journal of Steroid Biochemistry and Molecular Biology, 84(2-3), 149-157.