Vitamin D(3)-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.
McGuire
T F
TF
Department of Pharmacology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA. mcguire@server.pharm.pitt.edu
Trump
D L
DL
Johnson
C S
CS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002762:Cholecalciferol / Q000494:pharmacology*; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D002762:Cholecalciferol; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; D020169:Caspases