Liu X, Shi Y, Giranda VL, Luo Y.Inhibition of the
phosphatidylinositol 3-kinase/Akt pathway sensitizes MDA-MB468
human breast cancer cells to cerulenin-induced apoptosis.
Mol Cancer Ther. 2006 Mar;5(3):494-501
Department R47S, AP9A, Cancer Research, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064, USA.
Fatty acid synthase is overexpressed in cancer especially in
tumors with a poor prognosis. The specific fatty acid synthase
inhibitor cerulenin can induce apoptosis in cancer cells.
Likewise, phosphatidylinositol 3-kinase (PI3K)/Akt kinase
activities are elevated in primary tumors and cancer cell lines.
Here, we tested whether inhibition of PI3K/Akt pathway would
sensitize cancer cells to cerulenin-induced apoptosis. We show
that LY294002, an inhibitor of PI3K, sensitized MDA-MB468 breast
cancer cells to cerulenin-induced apoptosis. In MDA-MB468 cells,
cerulenin- and LY294002-mediated apoptosis was associated with
caspase-3 activation and the release of cytochrome c from
mitochondria to cytosol. In addition, we observed additional
species of Bak in mitochondria, suggesting a possible Bak
activation. Treatment of cells with cerulenin and LY294002
down-regulated the protein levels of X chromosome-linked
inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis 1
(cIAP-1), and Akt, whereas the levels of mitogen-activated
protein/extracellular signal-regulated kinase kinase and other
antiapoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xl) did not
change. Interestingly, the nonspecific caspase inhibitor, z-VAD-FMK,
inhibited the down-regulation of Akt, XIAP, and cIAP-1 in
cerulenin- and LY294002-treated cells. In conclusion, these
studies show that inhibition of PI3K can sensitize cerulenin-induced
apoptosis in MBA-MB468 breast cancer cells via activation of
caspases, down-regulation of antiapoptotic proteins, such as
XIAP, cIAP-1 and Akt, and possibly, activation of Bak in
mitochondria.
PMID: 16546963 |
