Journal
CELL CYCLE
Volume 8, Issue 20, Pages 3355-3364Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.8.20.9853
Keywords
hexokinase II; caspase-2; cisplatin; mitochondria
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Funding
- NCI NIH HHS [R01 CA118356, R01 CA118356-04] Funding Source: Medline
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Cancer cells are frequently glycolytic and overexpress hexokinase II (HXK II). In cancer cells, the majority of hexokinase II is localized to the mitochondria through interaction with the voltage dependent anion channel (VDAC). Disruption in the binding of hexokinase II to the mitochondria has been shown to promote mitochondrial injury provoked by pro-apoptotic proteins. The present study demonstrates that cisplatin induces the PIDD (p53 induced protein with a death domain) dependent activation of caspase-2. In turn, caspase-2 cleaves and activates Bid, resulting in the oligomerization of Bak and the release of cytochrome c. Notably, the detachment of hexokinase II from the mitochondria markedly potentiates the onset of caspase-2 induced mitochondrial damage, thus resulting in a synergistic induction of cisplatin induced cytotoxicity.
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