Vulnerability of Store-Operated Calcium Entry to Inhibitors and Microenvironment in Cells of Different Breast Cancer Subtypes

Abstract

The incidence and development of cancer are highly dependent on pathological disturbances in calcium homeostasis of the cell. One of the major pathways for calcium entry is store-operated calcium entry (SOCE), which functions in virtually all cell types. Changes in the expression level of the main proteins organizing SOCE are observed during the development of various cancer types, particularly breast cancer (BC). This leads to unique SOCE with characteristics individual for each type of BC and requires particular therapeutic approaches. In this study, we tested the sensitivity of SOCE in various BC cells to selective ORAI channel inhibitors and the less selective compounds Leflunomide and Teriflunomide, approved by the FDA for clinical use. We also analyzed the vulnerability of SOCE to the influence of factors typical of the tumor microenvironment: hypoxia and acidification. We have observed that the SOCE inhibitors Leflunomide and Teriflunomide suppress SOCE in the triple-negative BC cell line MDA-MB-231, but not in the luminal A BC cell line MCF-7. MDA-MB-231 cells also demonstrate higher pH dependence of SOCE compared to MCF-7 cells. In addition, the oxygen scavenger sodium dithionide also affects SOCE, stimulating it in MDA-MB-231 cells but inhibiting in MCF-7 cells. Overall, our data highlight the importance of considering the different sensitivities of various BC cell types to inhibitors and to microenvironmental factors such as hypoxia and acidification when developing targeted drugs.

Keywords

• breast cancer
• microenvironment
• hypoxia
• store-operated calcium entry
• Leflunomide
• Teriflunomide