Diet, autophagy, and cancer: a review.
ABSTRACT A host of dietary factors can influence various cellular processes and thereby potentially influence overall cancer risk and tumor behavior. In many cases, these factors suppress cancer by stimulating programmed cell death. However, death not only can follow the well-characterized type I apoptotic pathway but also can proceed by nonapoptotic modes such as type II (macroautophagy-related) and type III (necrosis) or combinations thereof. In contrast to apoptosis, the induction of macroautophagy may contribute to either the survival or death of cells in response to a stressor. This review highlights current knowledge and gaps in our understanding of the interactions among bioactive food constituents, autophagy, and cancer. Whereas a variety of food components including vitamin D, selenium, curcumin, resveratrol, and genistein have been shown to stimulate autophagy vacuolization, it is often difficult to determine if this is a protumorigenic or antitumorigenic response. Additional studies are needed to examine dose and duration of exposures and tissue specificity in response to bioactive food components in transgenic and knockout models to resolve the physiologic implications of early changes in the autophagy process.
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ABSTRACT: Progression of astrocytic tumors is, in part, related to their dysregulated autophagy capacity. Recent evidence indicates that upstream autophagy signaling events can be triggered by MT1-MMP, a membrane-bound matrix metalloproteinase that contributes to the invasive phenotype of brain cancer cells. The signaling functions of MT1-MMP require its intracellular domain, and recent identification of MTCBP-1, a cytoplasmic 19 kDa protein involved in the inhibition of MT1-MMP-mediated cell migration, suggests that modulation of MT1-MMP cytoplasmic domain-mediated signaling may affect other carcinogenic processes. Using qPCR and screening of cDNA generated from brain tumor tissues of grades I, II, III, and IV, MT1-MMP gene expression was found to correlate with increased grade of tumors. Inversely, MTCBP-1 expression decreased with increasing grade of brain tumor. Confocal microscopy and fluorescence resonance energy transfer (FRET) analysis revealed that overexpressing a cytoplasmic-deleted MT1-MMP recombinant protein mutant prevented MTCBP-1 recruitment to the intracellular leaf of plasma membrane in U87 glioblastoma cells. The interaction between MTCBP-1 and the 20 amino acids peptide representing the MT1-MMP cytoplasmic domain was confirmed by surface plasmon resonance. Overexpression of a full-length Wt-MT1-MMP triggered acidic autophagy vesicle formation and autophagic puncta formation for green fluorescent microtubule-associated protein 1 light chain 3 (GFP-LC3). Autophagic vesicles and GFP-LC3 puncta formation were abrogated in the presence of MTCBP-1. Our data elucidate a new role for MTCBP-1 regulating the intracellular function of MT1-MMP-mediated autophagy. The inverse correlation between MTCBP-1 and MT1-MMP expression with brain tumor grades could also contribute to the decreased autophagic index observed in high-grade tumors. © 2015 Wiley Periodicals, Inc.Molecular Carcinogenesis 01/2015; · 4.27 Impact Factor
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ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is a major killer worldwide and innovative measures are urgently warranted to lower the morbidity and mortality caused by this malignancy. Aberrant redox and metabolic status in HNSCC cells offer a unique opportunity to specifically target cancer cells. Therefore, we investigated the efficacy of grape seed extract (GSE) to target the redox and bioenergetic alterations in HNSCC cells. GSE treatment decreased the mitochondrial electron transport chain complex III activity, increased the mitochondrial superoxide levels and depleted the levels of cellular antioxidant (glutathione), thus resulting in the loss of mitochondrial membrane potential in human HNSCC Detroit 562 and FaDu cells. Polyethylene glycol-SOD addition reversed the GSE-mediated apoptosis without restoring complex III activity. Along with redox changes, GSE inhibited the extracellular acidification rate (representing glycolysis) and oxygen consumption rate (indicating oxidative phosphorylation) leading to metabolic stress in HNSCC cells. Molecular studies revealed that GSE activated AMP-activated protein kinase (AMPK), and suppressed Akt/mTOR/4E-BP1/S6K signaling in both Detroit 562 and FaDu cells. Interestingly, GSE increased the autophagic load specifically in FaDu cells, and autophagy inhibition significantly augmented the apoptosis in these cells. Consistent with in vitro results, in vivo analyses also showed that GSE feeding in nude mice activated AMPK and induced-autophagy in FaDu xenograft tumor tissues. Overall, these findings are innovative as we for the first time showed that GSE targets ETC complex III and induces oxidative and metabolic stress, thereby, causing autophagy and apoptotic death in HNSCC cells. © 2014 Wiley Periodicals, Inc.Molecular Carcinogenesis 12/2014; · 4.27 Impact Factor
- Journal of Pharmacological Sciences 01/2012; 119(2):150-159. · 2.11 Impact Factor