Resveratrol is a naturally occurring flavanoid with potent apoptosis-inducing activity against human tumor cells. We investigated the effect of resveratrol on human leukemia cell lines, in particular its ability to induce intracellular reactive oxygen species production and the effect of Bcl-2 overexpression on this model. Exposure of CEM cells to increasing concentrations of resveratrol (0-50 microM) resulted in an increase in mitochondrial superoxide production, decrease in transmembrane potential, and a concomitant decrease in cell viability. Whereas overexpression of Bcl-2 increased mitochondrial oxygen consumption and complex IV activity, CEM/Bcl-2 cells responded to the increased mitochondrial oxidative stress induced by resveratrol by significantly reducing mitochondrial respiration, complex IV activity, and O(2)(-) production, and promoted cell survival. The inhibitory effect of Bcl-2 on resveratrol-induced mitochondrial O(2)(-) production is further corroborated by the neutralization of this regulatory effect upon siRNA-mediated gene silencing of Bcl-2. These data provide evidence implicating mitochondrial metabolism in the anticancer activity of resveratrol, and underscore a novel regulatory role of Bcl-2 against exogenous oxidative stress through its ability to fine tune mitochondrial respiration, and by doing so maintaining mitochondrial O(2)(-) at a level optimal for survival.

Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform β (KIF1Bβ) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic XIAP-associated factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor (NGF) during development. KIF1Bβ is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1Bβ expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis. SIGNIFICANCE:KIF1Bβ has neuroblastoma tumor-suppressor properties and promotes and requires nuclear-localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1Bβ alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation. Cancer Discov; 4(4); 434-51.