Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis

Abstract

Components of garlic (Allium sativum) can cause disruption of microtubules, cell cycle arrest, and apoptosis in cancer cells. We show here that a water-soluble extract of garlic arrested MDA-MB-435 cancer cells in mitosis and caused apoptosis. The proapoptotic BH3-only, bcl-2 family protein Bim EL , which in healthy cells can be tightly sequestered to the microtubule-associated dynein motor complex, was modified after garlic treatment. The main effect of garlic on Bim EL was a considerable increase in a phosphorylated form of the protein. This phosphorylation(s), probably partly dependent on c-jun N-terminal kinase activity, promoted mitochondrial localisation of Bim EL . Furthermore, inhibition of extracellular signal-regulated kinases 1/2 increased the amount of another form of Bim EL present in the mitochondrial cellular fraction. Treatment of cells with the garlic compound diallyl disulphide had similar effects on Bim EL . The results indicate that the apoptotic effect of garlic and a combination of garlic and the inhibitor of extracellular signalregulated kinases 1/2 in MDA-MB-435 cells partly is due to modifications that are necessary for translocation of the proapoptotic protein Bim EL to mitochondria where it executes its proapoptotic function.

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“…MEK/ERK-mediated BimEL phosphorylation reportedly leads to proteasomal degradation, resulting in the suppression of proapoptotic effects (38)(39)(40)(41)(42). In the current study, we observed that the 23-kDa form of BimEL was degraded consistently in an MEK/ERK-dependent manner (Fig.…”

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“…Besides, the translocation of Bad to the mitochondria occurs in prostate cancer cells upon treatment with DATS (Xiao & Singh, 2006). When breast cancer MDA-MB-435 cells were exposed to water-soluble extracts (Lund et al, 2005), expression level, phosphorylation and mitochondrial localization of different isoforms of the BH3-only protein BimEL were altered. Interestingly, BimEL in normal physiological conditions is anchored to (and sequestered by) the MT complex (Chen, D. & Zhou, 2004;Lund et al, 2005).…”

“…When breast cancer MDA-MB-435 cells were exposed to water-soluble extracts (Lund et al, 2005), expression level, phosphorylation and mitochondrial localization of different isoforms of the BH3-only protein BimEL were altered. Interestingly, BimEL in normal physiological conditions is anchored to (and sequestered by) the MT complex (Chen, D. & Zhou, 2004;Lund et al, 2005). This may provide interesting insights about how the MT network is disrupted and the subsequent activation of the mitochondrial pathway may be interconnected.…”