Vitamin D and CaM Kinase Phosphatase Mediate Breast Cancer Proliferation

Abstract

The family of enzymes known as CaM Kinases have been shown to participate in cell signaling pathways in a variety of cell types including cancer cells. Ionomycin, carbachol and estrogen (E2) may increase intracellular calcium resulting in the activation of either CaM Kinase II (CaM KII) or CaM Kinase Kinase (CaM KK) and their substrates. Several agonists including E2 trigger calcium‐responsive pathways that regulate a number of transcription factors such as Elk‐1 leading to cell growth. CaM KK has been shown to activate numerous enzymes including CaM KI and ERK. In contrast, hormones Vitamin D (VitD) and thyroid hormone (T3) have been suggested to antagonize ERK activation and growth of certain cells, although the mechanism remains unknown. CaM Kinase Phosphatase (CaM KP) inactivates CaM KK and CaM KI, so we hypothesized that it may mediate the inhibitory effects of VitD and T3 in our cells. To the best of our knowledge, the specific role for CaM KP in E2 signaling in breast cancer cells has not been examined. Our results suggest that calcium‐mediated activation of CaM KK, CaM KI, and ERK leads to the growth of MDA‐MB‐231 (MDA) and MCF‐7 cells. VitD and T3 appear to inhibit E2 stimulation of CaM KI and ERK activity in MCF‐7 cells. Carbachol‐ and E2‐mediated cell growth was decreased by pretreatment of cells with VitD or T3. Interestingly, inhibition of CaM KP via siRNA knockdown reversed the inhibitory effect of VitD in our system. These results suggest that VitD and T3 may utilize CaM KP to antagonize calcium signaling through CaM KK and ERK in MDA and MCF‐7 cells.Support or Funding InformationJach Holman Endowment Fund at George Fox UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.