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PGC1? expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress.

ABSTRACT: Cancer cells reprogram their metabolism using different strategies to meet energy and anabolic demands to maintain growth and survival. Understanding the molecular and genetic determinants of these metabolic programs is critical to successfully exploit them for therapy. Here, we report that the oncogenic melanocyte lineage-specification transcription factor MITF drives PGC1? (PPARGC1A) overexpression in a subset of human melanomas and derived cell lines. Functionally, PGC1? positive melanoma cells exhibit increased mitochondrial energy metabolism and reactive oxygen species (ROS) detoxification capacities that enable survival under oxidative stress conditions. Conversely, PGC1? negative melanoma cells are more glycolytic and sensitive to ROS-inducing drugs. These results demonstrate that differences in PGC1? levels in melanoma tumors have a profound impact in their metabolism, biology, and drug sensitivity.

SUBMITTER: Vazquez F

PROVIDER: S-EPMC3708305 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress.

Vazquez Francisca F Lim Ji-Hong JH Chim Helen H Bhalla Kavita K Girnun Geoff G Pierce Kerry K Clish Clary B CB Granter Scott R SR Widlund Hans R HR Spiegelman Bruce M BM Puigserver Pere P

Cancer cell 20130214 3

Cancer cells reprogram their metabolism using different strategies to meet energy and anabolic demands to maintain growth and survival. Understanding the molecular and genetic determinants of these metabolic programs is critical to successfully exploit them for therapy. Here, we report that the oncogenic melanocyte lineage-specification transcription factor MITF drives PGC1α (PPARGC1A) overexpression in a subset of human melanomas and derived cell lines. Functionally, PGC1α positive melanoma cel ...[more]

PMID: 23416000

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Project description:Mitochondrial dysfunction plays a pivotal role in the progression of Alzheimer's disease (AD), and yet the mechanisms underlying the impairment of mitochondrial function in AD remain elusive. Recent evidence suggested a role for Presenilins (PS1 or PS2) in mitochondrial function. Mutations of PSs, the catalytic subunits of the ?-secretase complex, are responsible for the majority of inherited AD cases (FAD). PSs were shown to be present in mitochondria and particularly enriched in mitochondria-associated membranes (MAM), where PS2 is involved in the calcium shuttling between mitochondria and the endoplasmic reticulum (ER). We investigated the precise contribution of PS1 and PS2 to the bioenergetics of the cell and to mitochondrial morphology in cell lines derived from wild type (PS+/+), PS1/2 double knock-out (PSdKO), PS2KO and PS1KO embryos. Our results showed a significant impairment in the respiratory capacity of PSdKO and PS2KO cells with reduction of basal oxygen consumption, oxygen utilization dedicated to ATP production and spare respiratory capacity. In line with these functional defects, we found a decrease in the expression of subunits responsible for mitochondrial oxidative phosphorylation (OXPHOS) associated with an altered morphology of the mitochondrial cristae. This OXPHOS disruption was accompanied by a reduction of the NAD+/NADH ratio. Still, neither ADP/ATP ratio nor mitochondrial membrane potential (??) were affected, suggesting the existence of a compensatory mechanism for energetic balance. We observed indeed an increase in glycolytic flux in PSdKO and PS2KO cells. All these effects were truly dependent on PS2 since its stable re-expression in a PS2KO background led to a complete restoration of the parameters impaired in the absence of PS2. Our data clearly demonstrate here the crucial role of PS2 in mitochondrial function and cellular bioenergetics, pointing toward its peculiar role in the formation and integrity of the electron transport chain.

Dataset Information

PGC1? expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress.

Publications

PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress.

Similar Datasets

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