Abstract 4957: Mixed Lineage Kinase 3 mediates vanadium-induced cell death in cancer cells

Abstract

Abstract Vanadium is a transition metal and occurs naturally in a variety of minerals. In mammals, vanadium has been shown to promote cancer cell death and can also mimic insulin action, most probably through the inhibition of cellular tyrosine phosphatase and subsequent activation of signaling pathways. The mechanism by which vanadium causes cancer cell death is still not known. Interestingly, it has been shown that various mitogen activated protein kinase (MAPK) members are activated upon vanadium treatment. However, the contribution of any specific MAPK member that mediates vanadium-induced cell death has not been clearly delineated. It has been reported that JNK is activated by vanadium and therefore we investigated the role of Mixed Lineage Kinase 3 (MLK3) on vanadium-induced cell death. MLK3 is a MAP3K member that is known to specifically activate JNK pathway. We have earlier reported that MLK3 activation promotes cell death in cancer and neuronal cells. Our results demonstrated that endogenous MLK3 was activated by vanadium and MLK3 was highly phosphorylated on tyrosine residues. We also identified Src as a tyrosine kinase that phosphorylated MLK3 on specific tyrosine residues and phosphorylation of these tyrosine residues by Src was essential for MLK3 activation. Vanadium-induced cancer cell death was mediated by MLK3 or MLKs, because CEP-1347, a pan MLK inhibitor, prevented this cell death. Furthermore, the tyrosine phospho-deficient mutants of MLK3 also prevented vanadium-induced cell death. Interestingly, the activity of Src was seen to be in parallel with MLK3 kinase activity in human primary breast tumors. Taken together, our data demonstrate that tyrosine phosphorylation of MLK3 by oncogenic Src leads to MLK3 activation, which subsequently promotes vanadium-induced cell death in cancer cells. Our results also implicate a paradoxical pro-apoptotic role of Src in cancer cells, and thus it is conceivable that in tumors where both Src and MLK3/MLKs activities are higher, targeting of this axis might promote cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4957. doi:1538-7445.AM2012-4957