Polymethoxyflavones Activate Ca2+-Dependent Apoptotic Targets in Adipocytes
2009
Sergeev, Igor N. | Li, Shiming | Ho, Chi-Tang | Rawson, Nancy E. | Sushenkov, Slavik
Induction of apoptosis is an emerging strategy for the prevention and treatment of obesity because removal of adipocytes via apoptosis will result in reducing body fat and may help to maintain a long-lasting weight loss. Our previous studies have shown that a sustained increase in intracellular Ca2+ triggers apoptosis in various cell types via activation of Ca2+-dependent proteases and that the apoptosis-inducing effect of polymethoxyflavones (PMFs) in cancer cells is mediated through Ca2+ signaling. This paper reports that PMFs induce apoptosis in mature mouse 3T3-L1 adipocytes via activation of Ca2+-dependent calpain and Ca2+/calpain-dependent caspase-12. Treatment of adipocytes with PMFs evoked, in a concentration- and time-dependent fashion, sustained increase in the basal level of intracellular Ca2+. The increase in Ca2+ was associated with induction of apoptosis and activation of μ-calpain and caspase-12. Apoptosis-inducing activity of hydroxylated PMFs was significantly higher than that of the corresponding nonhydroxylated compounds. These results demonstrate that the apoptotic molecular targets activated by PMFs in adipocytes are Ca2+-dependent calpain and caspase-12. The findings obtained provide rationale for evaluating the role of PMFs in the prevention and treatment of obesity.
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