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Brain expressed X-linked ( Bex ) genes are newer group of pro-apoptotic genes. Role of any  Bex  gene in neuroblastoma and  Bex4  and  Bex6  in any cancer is completely unknown. Re-expression of all endogenous  Bex  genes by any nutraceutical is also unknown. Therefore, we investigated the induction of all endogenous  Bex  genes and associated mechanisms by curcumin using N2a, an aggressive neuroblastoma cell line. Curcumin induced all endogenous  Bex  genes prior to apoptosis in N2a cells in a dose- and time-dependent manner. Wortmannin (PI-3Kinases inhibitor), SP600125 (JNK inhibitor) and pifithrin-α (p53 inhibitor) abrogated curcumin-mediated induction of  Bex  genes. Inhibition of curcumin-mediated induction of  Bex  genes by pifithrin-α also inhibited N2a cells apoptosis suggesting, a direct role of  Bex  genes in N2a cells apoptosis and involvement of p53 in  Bex  genes induction. Curcumin treatment activated p53 through hyperphosphorylation at serine 15 before  Bex  genes induction indicating  Bex  genes are novel downstream targets of p53. Collectively, curcumin, a safe nutraceutical has the potential to induce all endogenous  Bex  genes to harness their anti-cancer properties in neuroblastoma cells. Re-expression of  Bex  genes by curcumin acts as tumor suppressors and may provide alternate strategy to treat neuroblastomas and other cancers with silenced  Bex  genes.

Induction of Bex genes by curcumin is associated with apoptosis and activation of p53 in N2a neuroblastoma cells