Apigenin down-regulates constitutive activation of AKT and induces apoptosis in primary effusion lymphoma cells

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The mechanisms that regulate mitogenic and antiapoptotic signals in primary effusion lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that apigenin (4’,5,7-trihydroxyflavone), a flavonoid, induces apoptosis of several PEL cell lines in a dose dependent manner. Such effects of apigenin appear to result from suppression of the constitutively active kinase AKT, and its effectors FOXO transcription factor and GSK3. Our data demonstrate that apigenin induces loss of mitochondrial membrane potential with subsequent release of cytochrome c and activation of caspase-3, followed by polyadenosin-5’-diphosphate-ribose polymerase (PARP) cleavage. In addition, zVAD-fmk, a universal inhibitor of caspases, prevents caspase-3 activation and abrogates cell death induced by apigenin treatment of PEL cells. Finally, treatment of PEL cells with apigenin down-regulated the expression of inhibitor of apoptosis protein (IAPs). Altogether, these data suggest a novel function for apigenin, acting as a suppressor of AKT/PKB pathway in PEL cells, and raise the possibility that this agent may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of the AKT/PKB pathway.