Vitamin D3-induced apoptosis of murine squamous cell carcinoma cells -: Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1

Vitamin D-3 inhibits cell growth and induces apoptosis in several human cancer lines in vitro and in vivo. However, little is known about the molecular events involved in vitamin D-3-induced apoptosis, Here, we demonstrate that the growth-promoting/pro-survival signaling molecule mitogen-activated protein kinase kinase (MEK) is cleaved in a caspase-dependent manner in murine squamous cell carcinoma (SCC) cells induced to undergo apoptosis by treatment with vitamin D-3. Cleavage resulted in nearly complete loss of full-length MEK and ERK1/2 phosphorylation. ERK1/2 expression was affected only slightly. The phosphorylation and expression of Akt, a kinase regulating a second cell survival pathway, was also inhibited after treatment with vitamin D-3. However, the pro-apoptotic signaling molecule MEKK-1 was up-regulated in both apoptotic and non-apoptotic cells with greater induction and partial N-terminal proteolysis of MEKK-1 observed in apoptotic cells. In contrast to vitamin D-3, cisplatin and etoposide down-regulated Akt levels only modestly, did not promote significant loss of MEK expression, and did not up-regulate MEKK-1. We propose that vitamin D-3 induces apoptosis in SCC cells by a unique mechanism involving selective caspase-dependent MEK cleavage and up-regulation of MEKK-1, Additional evidence is provided that vitamin D-3-induced apoptosis may be mediated via p38 MAPK.