The role of p38 MAP kinase in the synergistic cytotoxic action of calcitriol and TNF-α in human breast cancer cells

Calcitriol, the hormonal form of Vitamin D, potentiates the activity of some agents of the anti-cancer immune system including tumor necrosis factor-α (TNF-α). Different signaling pathways activated by TNF-α may be targets for calcitriol action. Activation of p38 MAP kinase was shown to have both pro- and anti-apoptotic actions in TNF-α-induced programmed cell death depending on cell context. Treatment of MCF-7 breast cancer cells with TNF-α resulted in activation of p38 MAP kinase that persisted for at least 24 h. Whereas calcitriol had no effect on the earlier phase of p38 MAP kinase activation (up to 1 h), it inhibited the activation of this pathway between one and 24 h after exposure to TNF-α. Both calcitriol and the p38 MAP kinase inhibitor SB203580 enhanced TNF-α-induced cytotoxicity and drop in mitochondrial membrane potential, but their combined effect was sub-additive. Taken together, these findings suggest that p38 MAP kinase plays an anti-apoptotic role in TNF-α-induced cytotoxicity in MCF-7 cells and that the synergistic interaction between TNF-α and calcitriol, leading to mitochondrial damage and subsequent cell death, is partially due to modulation of this signaling pathway.