Fatty acid synthase (FASN) is a key
enzyme that plays a critical role in numerous metabolic functions by catalyzing the synthesis for long-chain
fatty acids. FASN is highly expressed in various human
cancers. This preferential expression makes FASN an attractive target for anticancer
therapy.
Hexokinase II (HKII) is overexpressed in most
cancer cells, and it generally localizes to the outer mitochondrial membrane. Recent studies have demonstrated the protective role of mitochondrial HKII in preservation of mitochondrial integrity. The association of
hexokinase with mitochondria has emerged as a powerful mechanism in protecting numerous cell types against cell death. We performed this study to examine the mechanism underlying apoptosis induced by
cerulenin and with specific focus on its effect on HKII in ZR-75-1 human
breast cancer cells. Additionally, we sought to elucidate whether inhibition of the PI3K/Akt pathway can potentiate the anticancer effect of
cerulenin. Here, we showed that
cerulenin disrupts the physical association between HKII and AIF, leading to eventual cell death. In addition,
LY294002, a PI3K/Akt inhibitor, sensitized ZR-75-1
breast cancer cells to
cerulenin-induced apoptosis. Collectively,
cerulenin induces apoptosis via disrupting the interaction between AIF and HKII and inhibition of PI3K sensitizes cells to
cerulenin-induced apoptosis in ZR-75-1 cells.