Suppression of the vitamin D metabolizing enzyme CYP24A1 provides increased sensitivity to chemotherapeutic drugs in breast cancer

Kamiya,Sakura; Nakamori,Yuna; Takasawa,Akira; Takasawa,Kumi; Kyuno,Daisuke; Ono,Yusuke; Magara,Kazufumi; Osanai,Makoto

doi:10.3892/or.2023.8522

Suppression of the vitamin D metabolizing enzyme CYP24A1 provides increased sensitivity to chemotherapeutic drugs in breast cancer

Authors:
- Sakura Kamiya
- Yuna Nakamori
- Akira Takasawa
- Kumi Takasawa
- Daisuke Kyuno
- Yusuke Ono
- Kazufumi Magara
- Makoto Osanai
View Affiliations

Affiliations: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-0061, Japan
Published online on: March 10, 2023 https://doi.org/10.3892/or.2023.8522
Article Number: 85

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Vitamin D is an essential nutrient for the human body not only for the metabolism of calcium but also for homeostasis. Vitamin D contributes to cell fate decisions, including cell proliferation, differentiation and viability. Accumulated epidemiological data suggest a relationship between vitamin D deficiency and carcinogenesis in numerous organs. Furthermore, it is known that the expression of the vitamin D metabolizing enzyme, cytochrome P450 family 24 subtype A1 (CYP24A1), is increased in different types of human malignancy including breast carcinoma. However, the pathological relevance of elevated CYP24A1 expression level requires further clarification. In the present study, it was demonstrated that CYP24A1 promoted the oncogenic property of breast carcinoma cells. Consistent with previous reports, it was demonstrated that the expression of CYP24A1 was elevated in invasive breast carcinoma and significantly decreased the overall survival of patients with invasive breast carcinoma. Importantly, suppression of CYP24A1 expression significantly enhanced cell death sensitivity to two anticancer drugs with pharmacologically different modes of action, cisplatin and gefitinib. The results of the present study suggest the possibility of CYP24A1‑inhibiting therapy as a novel therapy in breast cancer with overexpression of CYP24A1.

View References

1	Bikle DD, Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, et al: Vitamin D: production, metabolism and mechanisms of action. 2021, Wilson DP: South Dartmouth (MA): MDText.com;
2	Bikle DD: Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 21:319–329. 2014. View Article : Google Scholar : PubMed/NCBI
3	Christakos S, Dhawan P, Verstuyf A, Verlinden L and Carmeliet G: Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 96:365–408. 2016. View Article : Google Scholar : PubMed/NCBI
4	Alshahrani F and Aljohani N: Vitamin D: Deficiency, sufficiency and toxicity. Nutrients. 5:3605–3616. 2013. View Article : Google Scholar : PubMed/NCBI
5	Saponaro F, Saba A and Zucchi R: An update on vitamin D metabolism. Int J Mol Sci. 21:65732020. View Article : Google Scholar : PubMed/NCBI
6	DeLuca HF: Vitamin D: Historical overview. Vitam Horm. 100:1–20. 2016. View Article : Google Scholar : PubMed/NCBI
7	Trump DL and Aragon-Ching JB: Vitamin D in prostate cancer. Asian J Androl. 20:244–252. 2018. View Article : Google Scholar : PubMed/NCBI
8	Carlberg C and Muñoz A: An update on vitamin D signaling and cancer. Semin Cancer Biol. 79:217–230. 2022. View Article : Google Scholar : PubMed/NCBI
9	Song ZY, Yao Q, Zhuo Z, Ma Z and Chen G: Circulating vitamin D level and mortality in prostate cancer patients: A dose-response meta-analysis. Endocr Connect. 7:R294–R303. 2018. View Article : Google Scholar : PubMed/NCBI
10	Dou R, Ng K, Giovannucci EL, Manson JE, Qian ZR and Ogino S: Vitamin D and colorectal cancer: Molecular, epidemiological and clinical evidence. Br J Nutr. 115:1643–1660. 2016. View Article : Google Scholar : PubMed/NCBI
11	Zhou J, Ge X, Fan X, Wang J, Miao L and Hang D: Associations of vitamin D status with colorectal cancer risk and survival. Int J Cancer. 149:606–614. 2021. View Article : Google Scholar : PubMed/NCBI
12	Negri M, Gentile A, de Angelis C, Montò T, Patalano R, Colao A, Pivonello R and Pivonello C: Vitamin D-induced molecular mechanisms to potentiate cancer therapy and to reverse drug-resistance in cancer cells. Nutrients. 12:17982020. View Article : Google Scholar : PubMed/NCBI
13	Mimori K, Tanaka Y, Yoshinaga K, Masuda T, Yamashita K, Okamoto M, Inoue H and Mori M: Clinical significance of the overexpression of the candidate oncogene CYP24 in esophageal cancer. Ann Oncol. 15:236–241. 2004. View Article : Google Scholar : PubMed/NCBI
14	Shiratsuchi H, Wang Z, Chen G, Ray P, Lin J, Zhang Z, Zhao L, Beer D, Ray D and Ramnath N: Oncogenic potential of CYP24A1 in lung adenocarcinoma. J Thorac Oncol. 12:269–280. 2017. View Article : Google Scholar : PubMed/NCBI
15	Osanai M and Lee GH: CYP24A1-induced vitamin D insufficiency promotes breast cancer growth. Oncol Rep. 36:2755–2762. 2016. View Article : Google Scholar : PubMed/NCBI
16	WHO Classification of Tumours Editorial Board (ed), . Breast tumours. Lyon (France): International Agency for Research on Cancer; 2019, (WHO classification of tumours series, 5th edition, volume 2).
17	Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J and Shi B: Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res. 5:2929–2943. 2015.PubMed/NCBI
18	Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, Viale G, Sotiriou C and Piccart M: Luminal B breast cancer: Molecular characterization, clinical management, and future perspectives. J Clin Oncol. 32:2794–2803. 2014. View Article : Google Scholar : PubMed/NCBI
19	Yin L, Duan JJ, Bian XW and Yu SC: Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 22:612020. View Article : Google Scholar : PubMed/NCBI
20	Zhang X, Harbeck N, Jeschke U and Doisneau-Sixou S: Influence of vitamin D signaling on hormone receptor status and HER2 expression in breast cancer. J Cancer Res Clin Oncol. 143:1107–1122. 2017. View Article : Google Scholar : PubMed/NCBI
21	Estébanez N, Gómez-Acebo I, Palazuelos C, Llorca J and Dierssen-Sotos T: Vitamin D exposure and risk of breast cancer: A meta-analysis. Sci Rep. 8:90392018. View Article : Google Scholar : PubMed/NCBI
22	Hossain S, Beydoun MA, Beydoun HA, Chen X, Zonderman AB and Wood RJ: Vitamin D and breast cancer: A systematic review and meta-analysis of observational studies. Clin Nutr ESPEN. 30:170–184. 2019. View Article : Google Scholar : PubMed/NCBI
23	Voutsadakis IA: Vitamin D receptor (VDR) and metabolizing enzymes CYP27B1 and CYP24A1 in breast cancer. Mol Biol Rep. 47:9821–9830. 2020. View Article : Google Scholar : PubMed/NCBI
24	Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Gordon D, Copeland T, D'Agostino D, et al: Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 380:33–44. 2019. View Article : Google Scholar : PubMed/NCBI
25	Park JW, Kim KA and Park JY: Effects of ketoconazole, a CYP4F2 inhibitor, and CYP4F2*3 genetic polymorphism on pharmacokinetics of vitamin K1. J Clin Pharmacol. 59:1453–1461. 2019. View Article : Google Scholar : PubMed/NCBI
26	Czyrski A, Resztak M, Świderski P, Brylak J and Główka FK: The overview on the pharmacokinetic and pharmacodynamic interactions of triazoles. Pharmaceutics. 13:19612021. View Article : Google Scholar : PubMed/NCBI
27	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
28	Segovia-Mendoza M, González-González ME, Barrera D, Díaz L and García-Becerra R: Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: Preclinical and clinical evidence. Am J Cancer Res. 5:2531–2561. 2015.PubMed/NCBI
29	Kim HJ, Lee YM, Ko BS, Lee JW, Yu JH, Son BH, Gong JY, Kim SB and Ahn SY: Vitamin D deficiency is correlated with poor outcomes in patients with luminal-type breast cancer. Ann Surg Oncol. 18:1830–1836. 2011. View Article : Google Scholar : PubMed/NCBI
30	Blackmore KM, Lesosky M, Barnett H, Raboud JM, Vieth R and Knight JA: Vitamin D from dietary intake and sunlight exposure and the risk of hormone-receptor-defined breast cancer. Am J Epidemiol. 168:915–924. 2008. View Article : Google Scholar : PubMed/NCBI
31	McCullough ML, Rodriguez C, Diver WR, Feigelson HS, Stevens VL, Thun MJ and Calle EE: Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the cancer prevention study II nutrition cohort. Cancer Epidemiol Biomark Prev. 14:2898–2904. 2005. View Article : Google Scholar : PubMed/NCBI
32	Kawase T, Matsuo K, Suzuki T, Hirose K, Hosono S, Watanabe M, Inagaki M, Iwata H, Tanaka H and Tajima K: Association between vitamin D and calcium intake and breast cancer risk according to menopausal status and receptor status in Japan. Cancer Sci. 101:1234–1240. 2010. View Article : Google Scholar : PubMed/NCBI