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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Providing alpha-ketoglutarate, oxaloacetate, or pyruvate rescues cancer cell proliferation under glutamine starvation, confirming that glutamine supports proliferation by replenishing depleted TCA cycle intermediates (anaplerosis).
“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
KRAS stimulates alanine aminotransferase activity, increasing alpha-ketoglutarate for the TCA cycle and mitochondrial ROS, which was required for mutant KRAS-driven lung tumorigenesis in mice.
“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]
A low level of reactive oxygen species activates tumorigenic growth signaling; when the level exceeds cellular redox capacity, ROS can damage macromolecules such as proteins, lipids and nucleotides.
“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 K-Ras mutant cells, oxygen consumption rate and ATP generation are enhanced by glutamine, contributing to tumorigenesis.
“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]
Mitochondrial pyruvate and mitochondrial alanine aminotransferase (ALT2) play a role in mediating glutamine anaplerosis.
“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
Mitochondrial ROS are necessary for KRAS-induced anchored-independent growth of lung cancer.
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · see citing works
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088 · see citing works
On Respiratory Impairment in Cancer Cells
Warburg, O. H. (1956) · Science · doi:10.1126/science.124.3215.269 · Cited by 3,472 · see citing works
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820 · see citing works
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622 · see citing works
Gao, P., Tchernyshyov, I., Chang, T.-C., Lee, Y.-S., Kita, K., Ochi, T., Zeller, K. I., De Marzo, A. M., Van Eyk, J. E., Mendell, J. T., et al. (2009) · Nature · doi:10.1038/nature07823 · Cited by 2,124 · see citing works
Wise, D. R., DeBerardinis, R. J., Mancuso, A., Sayed, N., Zhang, X.-Y., Pfeiffer, H. K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S. B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810199105 · Cited by 2,001 · see citing works
Hypoxia, HIF1 and glucose metabolism in the solid tumour
Denko, N. C. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2468 · Cited by 1,707 · see citing works
Fantin, V. R., St-Pierre, J., & Leder, P. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.04.023 · Cited by 1,635 · see citing works
Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice
Larsson, N.-G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., & Clayton, D. A. (1998) · Nature Genetics · doi:10.1038/ng0398-231 · Cited by 1,594 · see citing works
Cooperation and Competition in the Evolution of ATP-Producing Pathways
Pfeiffer, T., Schuster, S., & Bonhoeffer, S. (2001) · Science · doi:10.1126/science.1058079 · Cited by 1,365 · see citing works
Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells.
Reitzer, L. J., Wice, B. M., & Kennell, D. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)30124-2 · Cited by 1,240 · see citing works
c-Myc transactivation of <i>LDH-A</i> : Implications for tumor metabolism and growth
Shim, H., Dolde, C., Lewis, B. C., Wu, C.-S., Dang, G., Jungmann, R. A., Dalla-Favera, R., & Dang, C. V. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.13.6658 · Cited by 1,092 · see citing works
Meloche, S., & Pouysségur, J. (2007) · Oncogene · doi:10.1038/sj.onc.1210414 · Cited by 1,091 · see citing works
Tumor suppressors and cell metabolism: a recipe for cancer growth
Jones, R. G., & Thompson, C. B. (2009) · Genes & Development · doi:10.1101/gad.1756509 · Cited by 1,085 · see citing works
Trachootham, D., Zhou, Y., Zhang, H., Demizu, Y., Chen, Z., Pelicano, H., Chiao, P. J., Achanta, G., Arlinghaus, R. B., Liu, J., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.009 · Cited by 1,080 · see citing works
�ber den Stoffwechsel der Carcinomzelle
Warburg, O. (1924) · Die Naturwissenschaften · doi:10.1007/bf01504608 · Cited by 631 · see citing works
Mitochondrial tumour suppressors: a genetic and biochemical update
Gottlieb, E., & Tomlinson, I. P. M. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1737 · Cited by 617 · see citing works
Bell, E. L., Klimova, T. A., Eisenbart, J., Moraes, C. T., Murphy, M. P., Budinger, G. R. S., & Chandel, N. S. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200609074 · Cited by 568 · see citing works
Self-citationOn respiratory impairment in cancer cells
Weinhouse, S. (1956) · Science · doi:10.1126/science.124.3215.267 · Cited by 554 · see citing works
Uber den Stoffwechsel der Karzinomezellen
Warburg, O. (1924) · Medical Entomology and Zoology · Cited by 401 · see citing works
High aerobic glycolysis of rat hepatoma cells in culture: Role of mitochondrial hexokinase
Bustamante, E., & Pedersen, P. L. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.9.3735 · Cited by 396 · see citing works
Anchorage-independent cell growth signature identifies tumors with metastatic potential
Mori, S., Chang, J. T., Andrechek, E. R., Matsumura, N., Baba, T., Yao, G., Kim, J., Gatza, M. L., Murphy, S. K., & Nevins, J. R. (2009) · Oncogene · doi:10.1038/onc.2009.139 · Cited by 346 · see citing works
über den Stoffwechsel der Carcinomzelle
Warburg, O. H. (1925) · Journal of Molecular Medicine · doi:10.1007/bf01726151 · Cited by 257 · see citing works
Funes, J. M., Quintero, M., Henderson, S. R., Martínez, D., Qureshi, U., Westwood, C., Clements, M. O., Bourboulia, D., Pedley, R. B., Moncada, S., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700690104 · Cited by 256 · see citing works
Dhanasekaran, A., Kotamraju, S., Karunakaran, C., Kalivendi, S. V., Thomas, S., Joseph, J., & Kalyanaraman, B. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.04.016 · Cited by 189 · see citing works
Self-citationRegulation of Late G1/S Phase Transition and APCCdh1by Reactive Oxygen Species
Havens, C. G., Ho, A. L., Yoshioka, N., & Dowdy, S. F. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00303-06 · Cited by 182 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [20]Rana M, de Coo I, Diaz F, Smeets H, Moraes CT. An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. Ann Neurol. 2000;48:774–781. [PubMed] [Google Scholar]
Cited by
Sorted by citations
ROS function in redox signaling and oxidative stress
Schieber, M., & Chandel, N. S. (2014) · Current Biology · doi:10.1016/j.cub.2014.03.034 · Cited by 6,931 · see citing works
Self-citationMitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release
Zorov, D. B., Juhaszova, M., & Sollott, S. J. (2014) · Physiological Reviews · doi:10.1152/physrev.00026.2013 · Cited by 5,383 · see citing works
Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744 · see citing works
Mittler, R. (2017) · Trends in Plant Science · doi:10.1016/j.tplants.2016.08.002 · Cited by 3,499 · see citing works
Otto Warburg's contributions to current concepts of cancer metabolism
Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3038 · Cited by 3,427 · see citing works
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233 · see citing works
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013 · see citing works
Self-citationReactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03562-9 · Cited by 2,638 · see citing works
Wallace, D. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3365 · Cited by 2,404 · see citing works
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,316 · see citing works
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204 · see citing works
From Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119 · see citing works
The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism
Hoxhaj, G., & Manning, B. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0216-7 · Cited by 2,137 · see citing works
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R. M., Ferrone, C. R., Mullarky, E., Shyh-Chang, N., et al. (2013) · Nature · doi:10.1038/nature12040 · Cited by 1,990 · see citing works
Mitochondrial DNA stress primes the antiviral innate immune response
West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., et al. (2015) · Nature · doi:10.1038/nature14156 · Cited by 1,975 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Metabolic Pathways in Immune Cell Activation and Quiescence
Pearce, E. L., & Pearce, E. J. (2013) · Immunity · doi:10.1016/j.immuni.2013.04.005 · Cited by 1,692 · see citing works
Deconvoluting the context-dependent role for autophagy in cancer
White, E. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3262 · Cited by 1,698 · see citing works
Zielonka, J., Joseph, J., Sikora, A., Hardy, M., Ouari, O., Vasquez-Vivar, J., Cheng, G., Lopez, M., & Kalyanaraman, B. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00042 · Cited by 1,683 · see citing works
Self-citationThe return of metabolism: biochemistry and physiology of the pentose phosphate pathway
Stincone, A., Prigione, A., Cramer, T., Wamelink, M. M. C., Campbell, K., Cheung, E., Olin‐Sandoval, V., Grüning, N., Krüger, A., Tauqeer Alam, M., et al. (2015) · Biological Reviews · doi:10.1111/brv.12140 · Cited by 1,576 · see citing works
Autophagy and autophagy-related proteins in cancer
Li, X., He, S., & Ma, B. (2020) · Molecular Cancer · doi:10.1186/s12943-020-1138-4 · Cited by 1,653 · see citing works
Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?
Sabharwal, S. S., & Schumacker, P. T. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3803 · Cited by 1,643 · see citing works
The role of ROS in tumour development and progression
Cheung, E. C., & Vousden, K. H. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-021-00435-0 · Cited by 1,623 · see citing works
Cancer metabolism: a therapeutic perspective
Martinez-Outschoorn, U. E., Peiris-Pagés, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.60 · Cited by 1,505 · see citing works
The hallmarks of cancer metabolism: still emerging
Pavlova, N. N., Zhu, J., & Thompson, C. B. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.01.007 · Cited by 1,418 · see citing works
Metabolic pathways promoting cancer cell survival and growth
Boroughs, L. K., & DeBerardinis, R. J. (2015) · Nature Cell Biology · doi:10.1038/ncb3124 · Cited by 1,459 · see citing works
Targeting mitochondria metabolism for cancer therapy
Weinberg, S. E., & Chandel, N. S. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1712 · Cited by 1,385 · see citing works
Self-citationSena, L. A., Li, S., Jairaman, A., Prakriya, M., Ezponda, T., Hildeman, D. A., Wang, C.-R., Schumacker, P. T., Licht, J. D., Perlman, H., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.10.020 · Cited by 1,338 · see citing works
Self-citationActivated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis
Guo, J. Y., Chen, H.-Y., Mathew, R., Fan, J., Strohecker, A. M., Karsli-Uzunbas, G., Kamphorst, J. J., Chen, G., Lemons, J. M. S., Karantza, V., et al. (2011) · Genes & Development · doi:10.1101/gad.2016311 · Cited by 1,323 · see citing works
The role for autophagy in cancer
White, E. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73941 · Cited by 1,332 · see citing works
Reductive carboxylation supports growth in tumour cells with defective mitochondria
Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J. (2012) · Nature · doi:10.1038/nature10642 · Cited by 1,328 · see citing works
Self-citationZong, W., Rabinowitz, J. D., & White, E. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.011 · Cited by 1,287 · see citing works
Mitochondrial metabolism and cancer
Porporato, P. E., Filigheddu, N., Pedro, J. M. B., Kroemer, G., & Galluzzi, L. (2017) · Cell Research · doi:10.1038/cr.2017.155 · Cited by 1,292 · see citing works
Anastasiou, D., Poulogiannis, G., Asara, J. M., Boxer, M. B., Jiang, J., Shen, M., Bellinger, G., Sasaki, A. T., Locasale, J. W., Auld, D. S., et al. (2011) · Science · doi:10.1126/science.1211485 · Cited by 1,196 · see citing works
Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells
Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G. (2015) · Cell · doi:10.1016/j.cell.2015.07.017 · Cited by 1,173 · see citing works
The updated landscape of tumor microenvironment and drug repurposing
Jin, M.-Z., & Jin, W.-L. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00280-x · Cited by 1,262 · see citing works
ROS homeostasis and metabolism: a dangerous liason in cancer cells
Panieri, E., & Santoro, M. M. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.105 · Cited by 1,156 · see citing works
Oxidative Phosphorylation as an Emerging Target in Cancer Therapy
Ashton, T. M., McKenna, W. G., Kunz‐Schughart, L. A., & Higgins, G. S. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3070 · Cited by 1,144 · see citing works
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis
Wheaton, W. W., Weinberg, S. E., Hamanaka, R. B., Soberanes, S., Sullivan, L. B., Anso, E., Glasauer, A., Dufour, E., Mutlu, G. M., Budigner, G. S., et al. (2014) · eLife · doi:10.7554/elife.02242 · Cited by 1,105 · see citing works
Self-citationZandalinas, S. I., Fritschi, F., & Mittler, R. (2021) · Trends in Plant Science · doi:10.1016/j.tplants.2021.02.011 · Cited by 1,133 · see citing works
Metabolic regulation of cell growth and proliferation
Zhu, J., & Thompson, C. B. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0123-5 · Cited by 1,106 · see citing works
Brand, M. D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.001 · Cited by 1,063 · see citing works
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J. C., Tudawe, T., Seviour, E. G., San Lucas, F. A., et al. (2016) · eLife · doi:10.7554/elife.10250 · Cited by 927 · see citing works
How cancer metabolism is tuned for proliferation and vulnerable to disruption
Schulze, A., & Harris, A. L. (2012) · Nature · doi:10.1038/nature11706 · Cited by 927 · see citing works
Glutaminolysis: A Hallmark of Cancer Metabolism
Yang, L., Venneti, S., & Nagrath, D. (2017) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071516-044546 · Cited by 859 · see citing works
Role of Glutathione in Cancer: From Mechanisms to Therapies
Kennedy, L., Sandhu, J. K., Harper, M.-E., & Cuperlovic-Culf, M. (2020) · Biomolecules · doi:10.3390/biom10101429 · Cited by 880 · see citing works
Metabolism of immune cells in cancer
Leone, R. D., & Powell, J. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-020-0273-y · Cited by 877 · see citing works
We need to talk about the Warburg effect
DeBerardinis, R. J., & Chandel, N. S. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0172-2 · Cited by 864 · see citing works
Self-citationOncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., Frederick, D. T., Hurley, A. D., Nellore, A., Kung, A. L., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.003 · Cited by 818 · see citing works
Mitochondria as a therapeutic target for common pathologies
Murphy, M. P., & Hartley, R. C. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.174 · Cited by 832 · see citing works
The role of cellular reactive oxygen species in cancer chemotherapy
Yang, H., Villani, R. M., Wang, H., Simpson, M. J., Roberts, M. S., Tang, M., & Liang, X. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0909-x · Cited by 794 · see citing works
Mitochondrial reactive oxygen species and cancer
Sullivan, L. B., & Chandel, N. S. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-17 · Cited by 799 · see citing works
Self-citationEnvironment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer
Davidson, S. M., Papagiannakopoulos, T., Olenchock, B. A., Heyman, J. E., Keibler, M. A., Luengo, A., Bauer, M. R., Jha, A. K., O’Brien, J. P., Pierce, K. A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.007 · Cited by 737 · see citing works
Nrf2, the Master Regulator of Anti-Oxidative Responses
Vomund, S., Schäfer, A., Parnham, M., Brüne, B., & Von Knethen, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122772 · Cited by 752 · see citing works
Mitochondrial Metabolism as a Target for Cancer Therapy
Vasan, K., Werner, M., & Chandel, N. S. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.019 · Cited by 746 · see citing works
Self-citationTumor biomarkers for diagnosis, prognosis and targeted therapy
Zhou, Y., Tao, L., Qiu, J., Xu, J., Yang, X., Zhang, Y., Tian, X., Guan, X., Cen, X., & Zhao, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01823-2 · Cited by 772 · see citing works
KRAS: feeding pancreatic cancer proliferation
Bryant, K. L., Mancias, J. D., Kimmelman, A. C., & Der, C. J. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.12.004 · Cited by 675 · see citing works
Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy
Yang, Y., Karakhanova, S., Hartwig, W., D’Haese, J. G., Philippov, P. P., Werner, J., & Bazhin, A. V. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25349 · Cited by 671 · see citing works
Roesch, A., Vultur, A., Bogeski, I., Wang, H., Zimmermann, K. M., Speicher, D., Körbel, C., Laschke, M. W., Gimotty, P. A., Philipp, S. E., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.05.003 · Cited by 670 · see citing works
Autophagy, Metabolism, and Cancer
White, E., Mehnert, J. M., & Chan, C. S. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0490 · Cited by 669 · see citing works
Mitochondrial metabolism promotes adaptation to proteotoxic stress
Tsvetkov, P., Detappe, A., Cai, K., Keys, H. R., Brune, Z., Ying, W., Thiru, P., Reidy, M., Kugener, G., Rossen, J., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0291-9 · Cited by 645 · see citing works
The Complex Interplay between Antioxidants and ROS in Cancer
Harris, I. S., & DeNicola, G. M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.03.002 · Cited by 638 · see citing works
Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS
Zhang, W., Wang, G., Xu, Z., Tu, H.-Q., Hu, F., Dai, J., Chang, Y., Chen, Y., Lu, Y., Zeng, H., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.003 · Cited by 598 · see citing works
The Two Faces of Reactive Oxygen Species in Cancer
Reczek, C. R., & Chandel, N. S. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041916-065808 · Cited by 602 · see citing works
“F or p er so na l u se o nl y. regulate Kras-induced anchorage-independent growth of lung cancer cells through the MAPK/ERK pathway (Weinberg et al. 2010).”
BackgroundInfluentialSelf-citationThe dynamic nature of autophagy in cancerPreprint
Kimmelman, A. C. (2011) · Genes & Development · doi:10.1101/gad.17558811 · Cited by 587 · see citing works
BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis
Wiel, C., Le Gal, K., Ibrahim, M. X., Jahangir, C. A., Kashif, M., Yao, H., Ziegler, D. V., Xu, X., Ghosh, T., Mondal, T., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.005 · Cited by 579 · see citing works
The role of nuclear lamin B1 in cell proliferation and senescence
Shimi, T., Butin-Israeli, V., Adam, S. A., Hamanaka, R. B., Goldman, A. E., Lucas, C. A., Shumaker, D. K., Kosak, S. T., Chandel, N. S., & Goldman, R. D. (2011) · Genes & Development · doi:10.1101/gad.179515.111 · Cited by 547 · see citing works
Self-citationA Mitochondrial Switch Promotes Tumor Metastasis
Porporato, P. E., Payen, V. L., Pérez‐Escuredo, J., Saedeleer, C. J. D., Danhier, P., Copetti, T., Dhup, S., Tardy, M., Vazeille, T., Bouzin, C., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.06.043 · Cited by 571 · see citing works
Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets
Park, J. H., Pyun, W. Y., & Park, H. W. (2020) · Cells · doi:10.3390/cells9102308 · Cited by 558 · see citing works
ROS in Cancer: The Burning Question
Chio, I. I. C., & Tuveson, D. A. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.004 · Cited by 532 · see citing works
Increased demand for NAD(+) relative to ATP drives aerobic glycolysis
Luengo, A., Li, Z., Gui, D. Y., Sullivan, L. B., Zagorulya, M., Do, B. T., Ferreira, R., Naamati, A., Ali, A., Lewis, C. A., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2020.12.012 · Cited by 547 · see citing works
Mitochondria as playmakers of apoptosis, autophagy and senescence
Abate, M., Festa, A., Falco, M., Lombardi, A., Luce, A., Grimaldi, A., Zappavigna, S., Sperlongano, P., Irace, C., Caraglia, M., et al. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.022 · Cited by 543 · see citing works
Duch, M. C., Budinger, G. R. S., Liang, Y. T., Soberanes, S., Urich, D., Chiarella, S. E., Campochiaro, L. A., Gonzalez, A., Chandel, N. S., Hersam, M. C., et al. (2011) · Nano Letters · doi:10.1021/nl202515a · Cited by 546 · see citing works
Self-citationIron and cancer: recent insights
Manz, D. H., Blanchette, N. L., Paul, B. T., Torti, F. M., & Torti, S. V. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13008 · Cited by 507 · see citing works
Oxidative cell death in cancer: mechanisms and therapeutic opportunities
An, X., Yu, W., Liu, J., Tang, D., Li, Y., & Chen, X. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06939-5 · Cited by 568 · see citing works
Oxidative stress and pulmonary fibrosis
Cheresh, P., Kim, S.-J., Tulasiram, S., & Kamp, D. W. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.11.021 · Cited by 527 · see citing works
Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma?
Jose, C., Bellance, N., & Rossignol, R. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.10.012 · Cited by 518 · see citing works
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527 · see citing works
Analysis and Interpretation of Microplate-Based Oxygen Consumption and pH Data
Divakaruni, A. S., Paradyse, A. R., Ferrick, D. A., Murphy, A. N., & Jastroch, M. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-801415-8.00016-3 · Cited by 525 · see citing works
TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions
Martínez‐Reyes, I., Diebold, L. P., Kong, H., Schieber, M., Huang, H., Hensley, C. T., Mehta, M., Wang, T., Santos, J. H., Woychik, R. P., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.12.002 · Cited by 512 · see citing works
Self-citationInterplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy
Poillet-Perez, L., Despouy, G., Delage-Mourroux, R., & Boyer-Guittaut, M. (2015) · Redox Biology · doi:10.1016/j.redox.2014.12.003 · Cited by 503 · see citing works
Cancer and Inflammation: An Old Intuition with Rapidly Evolving New Concepts
Trinchieri, G. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075008 · Cited by 506 · see citing works
Reactive Oxygen Species in the Tumor Microenvironment: An Overview
Weinberg, F., Ramnath, N., & Nagrath, D. (2019) · Cancers · doi:10.3390/cancers11081191 · Cited by 502 · see citing works
Self-citationMitochondrial Dysfunction in Cancer
Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00292 · Cited by 502 · see citing works
Targeting antioxidants for cancer therapy
Glasauer, A., & Chandel, N. S. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.07.017 · Cited by 502 · see citing works
Self-citationMetabolism of tissue macrophages in homeostasis and pathology
Wculek, S. K., Dunphy, G., Heras-Murillo, I., Mastrangelo, A., & Sancho, D. (2022) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00791-9 · Cited by 501 · see citing works
Oncogenic K‐Ras decouples glucose and glutamine metabolism to support cancer cell growth
Gaglio, D., Metallo, C. M., Gameiro, P. A., Hiller, K., Danna, L. S., Balestrieri, C., Alberghina, L., Stephanopoulos, G., & Chiaradonna, F. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.56 · Cited by 492 · see citing works
Lactate and lactylation in cancer
Chen, J., Huang, Z., Chen, Y., Tian, H., Chai, P., Shen, Y., Yao, Y., Xu, S., Ge, S., & Jia, R. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02082-x · Cited by 524 · see citing works
Phan, L. M., Yeung, S. J., & Lee, M. H. (2014) · Europe PMC (PubMed Central) · doi:10.7497/j.issn.2095-3941.2014.01.001 · Cited by 500 · see citing works
Cellular Metabolic Stress: Considering How Cells Respond to Nutrient Excess
Wellen, K. E., & Thompson, C. B. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.10.004 · Cited by 486 · see citing works
Nucleotide metabolism: a pan-cancer metabolic dependency
Mullen, N. J., & Singh, P. K. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00557-7 · Cited by 475 · see citing works
Cancer as a metabolic disease: implications for novel therapeutics
Seyfried, T. N., Flores, R. E., Poff, A. M., & D’Agostino, D. P. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt480 · Cited by 472 · see citing works
Metabolic Regulation in Pluripotent Stem Cells during Reprogramming and Self-Renewal
Zhang, J., Nuebel, E., Daley, G. Q., Koehler, C. M., & Teitell, M. A. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.10.005 · Cited by 465 · see citing works
The multifaceted role of reactive oxygen species in tumorigenesis
Kirtonia, A., Sethi, G., & Garg, M. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03536-5 · Cited by 452 · see citing works
Tumor glycolysis, an essential sweet tooth of tumor cells
Paul, S., Ghosh, S., & Kumar, S. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.09.007 · Cited by 449 · see citing works
Jeong, S. M., Xiao, C., Finley, L. W. S., Lahusen, T., Souza, A. L., Pierce, K., Li, Y.-H., Wang, X., Laurent, G., German, N. J., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.024 · Cited by 445 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
