Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

Pélicano, Hélène; Xu, Rui‐Hua; Du, Min; Li, Feng; Sasaki, Ryohei; Carew, Jennifer S.; Hu, Yumin; Ramdas, Latha; Hu, Limei; Keating, Michael J.; Zhang, Wei; Plunkett, William; Huang, Peng

doi:10.1083/jcb.200512100

Cited by 354 publications

(326 citation statements)

References 34 publications

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“…Many cancer cells, including melanoma cells, have mitochondrial respiration defects and suppressed mitochondrial function [53]. We observed a similar situation in some metastatic melanomas investigated in our study.…”

Section: Discussionsupporting

confidence: 87%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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Section: Discussionsupporting

confidence: 87%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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“…Importantly, the phosphoinositide 3-kinase-AKT pathway is one of the major cellular pathways for survival and proliferation (Pelicano et al, 2006). Frequently, tumourigenesis is associated with de-regulation of transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

et al. 2010

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“…Respiration rate is a determinant of oxygen consumption coupled with CO 2 production, which is indicative of the activity of mitochondrial oxidative phosphorylation. 21,22 Figure 1 shows the design of this study. We uncovered that ATP production and the activity of mitochondrial respiratory chain were compromised for all cell lines upon sublethal nAg exposure.…”

mentioning

confidence: 99%

Nanosilver Incurs an Adaptive Shunt of Energy Metabolism Mode to Glycolysis in Tumor and Nontumor Cells

Chen

Wang

et al. 2014

ACS Nano

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anomaterials are currently used in a wide range of products with more prospective applications; however, people raised concerns about their safety profiles. This is because nanomaterials have novel physicochemical properties that can interact with biological systems to generate toxicity. 1 To date, most studies have focused on cytotoxicity of nanomaterials at high concentrations that incur significant injuries to cells in vitro and in animals; however, the high dosage used is often not realistic and fails to consider the potentially detrimental effects on human health under chronic lowdose exposure settings, such as everyday and environmental exposure. 2 Thus, research is urgently needed to study the biological effects at sublethal or even nontoxic concentrations. Nanosilver (nAg), a material that is well-known for its antimicrobial properties, has been extensively used in a wide range of biomedical and consumer products. 3À6 Although many studies have been performed to investigate the cytotoxicity of nAg under different settings, 7À9 relatively little study has been conducted to understand the biological effects of nAg under nontoxic concentrations, which likely precede the toxicological processes or can be differentiated from cytotoxic effects but could perturb cellular homeostasis.Under normal conditions, cells maintain a balanced energy homeostasis through concertedly regulated signaling and metabolic pathways. Namely, there is a perfect equilibrium between anabolism and catabolism

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Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

Cited by 354 publications

References 34 publications

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

Nanosilver Incurs an Adaptive Shunt of Energy Metabolism Mode to Glycolysis in Tumor and Nontumor Cells

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