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.

Introduction Diabetes self-management education is a key aspect in the long-term management of type 2 diabetes. The patient and healthcare professional (HCP) perspective on the use of technology-assisted DSME has yet to be studied. Hence, the objective of this study was to better understand the factors that facilitate or hinder the adoptions of such education by adults with type 2 diabetes and their HCPs. Methods We systematically searched five databases (Medline, Embase, CINAHL, Web of Science Core Collection, and PsycINFO) until August 2019. The search included qualitative and mixed-method studies that reported the views of patients and HCPs regarding features, uses, and implementations of technology-assisted DSME. Data were synthesized through an inductive thematic analysis. Results A total of 13 articles were included, involving 242 patients, ranging from 18 to 81 years and included web-based, mobile application, digital versatile disc (DVD), virtual reality or telehealth interventions. Patients and HCPs had mixed views towards features of the technology-assisted interventions, with patients' personal qualities and HCPs' concerns affecting uses of the interventions. Patients generally preferred technologies that were easy to access, use, and apply and that had reliable information. Patients' ambitions motivated them, and personal attributes such as poor competence with technology, poor literacy, and language barriers acted as barriers. Patients especially liked the peer support that they

Cancer is one of the most studied areas of human biology over the past century. Despite having attracted much attention, hype, and investments, the search to find a cure for cancer remains an uphill battle. Recent discoveries that challenged the central dogma of molecular biology not only further increase the complexity but also demonstrate how various types of noncoding RNAs such as microRNA and long noncoding RNA, as well as their related processes such as RNA editing, are important in regulating gene expression. Parallel to this aspect, an increasing number of reports have focused on a family of proteins known as DEAD/H-box helicases involved in RNA metabolism, regulation of long and short noncoding RNAs, and novel roles as "editing helicases" and their association with cancers. This review summarizes recent findings on the roles of RNA helicases in various cancers, which are broadly classified into adult solid tumors, childhood solid tumors, leukemia, and cancer stem cells. The potential small molecule inhibitors of helicases and their therapeutic value are also discussed. In addition, analyzing next-generation sequencing data obtained from public portals and reviewing existing literature, we provide new insights on the potential of DEAD/H-box helicases to act as pharmacological drug targets in cancers.

KIF1Bβ is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1Bβ activates the Ca(2+)-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca(2+) signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1Bβ affects mitochondrial dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondrial fission and apoptosis. Furthermore, KIF1Bβ actuates recognition of all known CN substrates, implying a general mechanism for KIF1Bβ in Ca(2+) signaling and how Ca(2+)-dependent signaling is executed by CN. Pathogenic KIF1Bβ mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1Bβ and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondrial dynamics contributes to high-risk and poor-prognosis neuroblastoma.

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Apoptosis (programmed cell death) is a systematic and coordinated cellular process that occurs in physiological and pathophysiological conditions. Sidestepping or resisting apoptosis is a distinct characteristic of human cancers including childhood malignancies. This review dissects the apoptosis pathways implicated in pediatric tumors. Understanding these pathways not only unraveled key molecules that may serve as potential targets for drug discovery, but also molecular nodes that integrate with other signaling networks involved in processes such as development. This review presents current knowledge of the complex regulatory system that governs apoptosis with respect to other processes in pediatric cancers, so that fresh insights may be derived regarding treatment resistance or for more effective treatment options.

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