A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3.
Increased production of mitochondrion-derived reactive oxygen species (ROS) is characteristic of a metabolic shift observed during malignant transformation. While the exact sources and roles of ROS in tumorigenesis remain to be defined, it has become clear that maintaining redox balance is critical for cancer cell proliferation and survival and, as such, may represent a vulnerability that can be exploited therapeutically. STAT3, a latent cytosolic transcription factor activated by diverse cytokines and growth factors, has been shown to exhibit an additional, nontranscriptional function in mitochondria, including modulation of electron transport chain activity. In particular, malignant transformation by Ras oncogenes exploits mitochondrial STAT3 functions. We used mass spectrometry-based metabolomics profiling to explore the biochemical basis for the STAT3 dependence of Ras transformation. We identified the gamma-glutamyl cycle, the production of glutathione, and the regulation of ROS as a mitochondrion-STAT3-dependent pathway in Ras-transformed cells. Experimental inhibition of key enzymes in the glutathione cycle resulted in the depletion of glutathione, accumulation of ROS, oxidative DNA damage, and cell death in an oncogenic Ras- and mitochondrial STAT3-dependent manner. These data uncover a synthetic lethal interaction involving glutathione production and mitochondrial ROS regulation in Ras-transformed cells that is governed by mitochondrial STAT3 and might be exploited therapeutically.
STAT Cancer Biology Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia Monash University, Clayton, Victoria, Australia.
Daniel J
DJ
Garama
STAT Cancer Biology Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia Monash University, Clayton, Victoria, Australia.
Tiffany J
TJ
Harris
STAT Cancer Biology Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia Monash University, Clayton, Victoria, Australia.
Christine L
CL
White
Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
Fernando J
FJ
Rossello
New York University School of Medicine, New York, New York, USA.
Maher
M
Abdul-Hay
New York University School of Medicine, New York, New York, USA STAT Cancer Biology Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia Monash University, Clayton, Victoria, Australia daniel.gough@hudson.org.au david.levy@nyumc.org.
Daniel J
DJ
Gough
New York University School of Medicine, New York, New York, USA daniel.gough@hudson.org.au david.levy@nyumc.org.
David E
DE
Levy
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011905:Genes, ras; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D005723:gamma-Glutamyltransferase; D005978:Glutathione