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Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
Open accessAbstract
Otto Warburg's theory on the origins of cancer postulates that tumor cells have defects in mitochondrial oxidative phosphorylation and therefore rely on high levels of aerobic glycolysis as the major source of ATP to fuel cellular proliferation (the Warburg effect). This is in contrast to normal cells, which primarily utilize oxidative phosphorylation for growth and survival. Here we report that the major function of glucose metabolism for Kras-induced anchorage-independent growth, a hallmark of transformed cells, is to support the pentose phosphate pathway. The major function of glycolytic ATP is to support growth under hypoxic conditions. Glutamine conversion into the tricarboxylic acid cycle intermediate alpha-ketoglutarate through glutaminase and alanine aminotransferase is essential for Kras-induced anchorage-independent growth. Mitochondrial metabolism allows for the generation of reactive oxygen species (ROS) which are required for Kras-induced anchorage-independent growth through regulation of the ERK MAPK signaling pathway. We show that the major source of ROS generation required for anchorage-independent growth is the Q o site of mitochondrial complex III. Furthermore, disruption of mitochondrial function by loss of the mitochondrial transcription factor A (TFAM) gene reduced tumorigenesis in an oncogenic Kras-driven mouse model of lung cancer. These results demonstrate that mitochondrial metabolism and mitochondrial ROS generation are essential for Kras-induced cell proliferation and tumorigenesis.
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“Providing cells with αKG, oxaloacetate, or pyruvate is sufficient to rescue cancer cell proliferation in conditions of glutamine starvation, confirming that glutamine supports proliferation by replenishing depleted TCA cycle intermediates, a process termed anaplerosis (Altman et al., 2016; Weinberg et al., 2010; Yuneva et al., 2007).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Weinberg et al., 2010
In the citing paper
“However, KRAS has also been shown to promote cancer cell growth by stimulating alanine aminotransferase activity, leading to high levels of α-ketoglutarate for the TCA cycle and mitochondrial ROS generation, which was required for mutant KRAS-driven tumorigenesis in a mouse model of lung cancer64.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [64]
In the citing paper
“A low level of reactive oxygen species (ROS) activates tumorigenic growth signaling; however, when the level exceeds the cellular redox capacity, ROS can damage macromolecules such as proteins, lipids and nucleotides55.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [55]
In the citing paper
“Correspondingly, in K-Ras mutant cells, the oxygen consumption rate and ATP generation are enhanced by glutamine, contributing to tumorigenesis55.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [55]
In the citing paper
“Notably, alanine levels were significantly decreased in Mpc knockdown cells, highlighting a role for mitochondrial pyruvate and mitochondrial alanine aminotransferase (ALT2) in mediating glutamine anaplerosis which was previously described in cancer cells (Weinberg et al., 2010).”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Weinberg et al., 2010
In the citing paper
“Another study reported that mitochondrial ROS are necessary for the KRAS (Kirsten rat sarcoma virus)—induced anchored-independent growth of lung cancer.”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Weinberg et al. 2010
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Metadata
- Authors
- Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R. S., & Chandel, N. S.
- Affiliations
- Northwestern University (US)
- Division of Pulmonary and Critical Care, Department of Medicine,
- Medical College of Wisconsin (US)
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-26
- Volume
- 107
- Issue
- 19
- Pages
- 8788-8793
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2889315
- OpenAlex
- W1982330633
- Cited by
- 1,742
- References
- 29
- Citations by year
- 2026: 63 · 2025: 100 · 2024: 124 · 2023: 122 · 2022: 149 · 2021: 154 · 2020: 137 · 2019: 138 · 2018: 111 · 2017: 108 · 2016: 100 · 2015: 113 · 2014: 89 · 2013: 77 · 2012: 77
- FWCI
- 23.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000201)
- LUNGevity Foundation
- Respiratory Health Association of Metropolitan Chicago
- Respiratory Health Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL071643)
- National Cancer Institute (R01CA125112, R01CA152810, R01CA123067, CA125112, P30CA060553, T32CA070085, T32CA009560)
- National Institute of Environmental Health Sciences (ES 013995, ES015024, R01ES013995, R01ES015024)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- KRAS, mitochondrial metabolism, reactive oxygen species, pentose phosphate pathway, aerobic glycolysis, Warburg effect, anchorage-independent growth, glutaminase, alpha-ketoglutarate, TCA cycle, ERK signaling, mitochondrial complex III, TFAM, lung cancer, carcinogenesis, hypoxia
- MeSH terms
- Aerobiosis, Animals, Cell Adhesion, Cell Transformation, Neoplastic, Glutamine, Glycolysis, Humans, Lung Neoplasms, Mitochondria, Oxidative Phosphorylation, Pentose Phosphate Pathway, Electron Transport Complex III, Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, HCT116 Cells, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Mice
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