PGC1α Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress

• Published in: Cancer cell Vol. 23; no. 3; pp. 287 - 301
• Main Authors: Vazquez, Francisca, Lim, Ji-Hong, Chim, Helen, Bhalla, Kavita, Girnun, Geoff, Pierce, Kerry, Clish, Clary B., Granter, Scott R., Widlund, Hans R., Spiegelman, Bruce M., Puigserver, Pere
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.03.2013
• Subjects: Animals; Apoptosis; Cell Line, Tumor; Energy Metabolism; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HEK293 Cells; Humans; Melanocytes - metabolism; Melanoma - metabolism; Mice; Microphthalmia-Associated Transcription Factor - metabolism; Mitochondria - metabolism; Oxidative Stress; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2012.11.020

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 cells exhibit increased mitochondrial energy metabolism and reactive oxygen species (ROS) detoxification capacities that enable survival under oxidative stress conditions. Conversely, PGC1α negative melanoma cells are more glycolytic and sensitive to ROS-inducing drugs. These results demonstrate that differences in PGC1α levels in melanoma tumors have a profound impact in their metabolism, biology, and drug sensitivity. [Display omitted] ► PGC1α is elevated in a subset of human melanoma tumors and derived cell lines ► PGC1α-positive melanoma cells exhibit increased mitochondrial metabolism ► PGC1α-positive melanoma cells exhibit increased ROS detoxification capacity ► PGC1α-negative melanoma cells are more glycolytic and sensitive to ROS-inducing drugs