Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of Braf V600E–Driven Lung Tumors
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Abstract
UNLABELLED: Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BrafV600E-induced lung cancer in the presence or absence of the tumor suppressor Trp53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 had no additive effect, suggesting that both genes modulate tumorigenesis by regulating oxidative stress and revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, Atg7 deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse life span. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire and survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains BrafV600E tumor growth and metabolism. SIGNIFICANCE: The essential autophagy gene Atg7 functions to promote BrafV600E-driven lung tumorigenesis by preserving mitochondrial glutamine metabolism. This suggests that inhibiting autophagy is a novel approach to treating BrafV600E-driven cancers.
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Deletion of Atg7 changes lung tumors driven by KrasG12D and BrafV600E from malignant adenocarcinomas to benign oncocytomas.
“deletion of a core component of the autophagy machinery, Atg7, was shown to dramatically change the nature of lung tumors driven by KrasG12D and BrafV600E oncogenes from malignant adenocarcinomas to benign oncocytomas”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Strohecker et al., 2013
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Cites
Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674 · see citing works
The role of autophagy during the early neonatal starvation period
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., & Mizushima, N. (2004) · Nature · doi:10.1038/nature03029 · Cited by 2,865 · see citing works
Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y., Ueno, I., Sakamoto, A., Tong, K. I., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2021 · Cited by 2,422 · see citing works
Impairment of starvation-induced and constitutive autophagy in <i>Atg7</i> -deficient mice
Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200412022 · Cited by 2,331 · see citing works
Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E.-L., Mizushima, N., Ohsumi, Y., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci20039 · Cited by 2,311 · see citing works
Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., et al. (2011) · Nature · doi:10.1038/nature10189 · Cited by 2,277 · see citing works
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224 · see citing works
Yue, Z., Jin, S., Yang, C., Levine, A. J., & Heintz, N. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2436255100 · Cited by 2,116 · see citing works
Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis
Degenhardt, K., Mathew, R., Beaudoin, B., Bray, K., Anderson, D., Chen, G., Mukherjee, C., Shi, Y., Gélinas, C., Fan, Y., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.06.001 · Cited by 2,013 · see citing works
Self-citationRabinowitz, J. D., & White, E. (2010) · Science · doi:10.1126/science.1193497 · Cited by 1,982 · see citing works
Self-citationIsolation and characterization of autophagy‐defective mutants of Saccharomyces cerevisiae
Tsukada, M., & Ohsumi, Y. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)80398-e · Cited by 1,756 · see citing works
High frequency of BRAF mutations in nevi
Pollock, P. M., Harper, U. L., Hansen, K. S., Yudt, L. M., Stark, M., Robbins, C. M., Moses, T. Y., Hostetter, G., Wagner, U., Kakareka, J., et al. (2003) · Nature Genetics · doi:10.1038/ng1054 · Cited by 1,730 · see citing works
Autophagy Suppresses Tumorigenesis through Elimination of p62
Mathew, R., Karp, C. M., Beaudoin, B., Vuong, N., Chen, G., Chen, H.-Y., Bray, K., Reddy, A., Bhanot, G. V., Gélinas, C., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.048 · Cited by 1,723 · see citing works
Self-citationDeconvoluting 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
Self-citationPancreatic cancers require autophagy for tumor growth
Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., Bause, A., Li, Y., Stommel, J. M., Dell'Antonio, G., et al. (2011) · Genes & Development · doi:10.1101/gad.2016111 · Cited by 1,498 · see citing works
Autophagy-deficient mice develop multiple liver tumors
Takamura, A., Komatsu, M., Hara, T., Sakamoto, A., Kishi, C., Waguri, S., Eishi, Y., Hino, O., Tanaka, K., & Mizushima, N. (2011) · Genes & Development · doi:10.1101/gad.2016211 · Cited by 1,342 · cited 9× · see citing works
“HBSS: 0 1 2 3 0 1 2 3 5078(2) #2 5078(2) #3 5079(2) #2 5079(3) #1 5125(1) #2 5125(1) #5 5311(2) #10 5317(1) #5”
InfluentialActivated 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
Self-citationAutophagy suppresses tumor progression by limiting chromosomal instabilityPreprint
Mathew, R., Kongara, S., Beaudoin, B., Karp, C. M., Bray, K., Degenhardt, K., Chen, G., Jin, S., & White, E. (2007) · Genes & Development · doi:10.1101/gad.1545107 · Cited by 938 · see citing works
Self-citationPrinciples and Current Strategies for Targeting Autophagy for Cancer Treatment
Amaravadi, R. K., Lippincott‐Schwartz, J., Yin, X., Weiss, W. A., Takebe, N., Timmer, W. C., DiPaola, R. S., Lotze, M. T., & White, E. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2634 · Cited by 899 · see citing works
Self-citationLau, A., Wang, X.-J., Zhao, F. L., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E., & Zhang, D. D. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00248-10 · Cited by 851 · see citing works
Self-citationAutophagy mitigates metabolic stress and genome damage in mammary tumorigenesisPreprint
Karantza‐Wadsworth, V., Patel, S. A., Kravchuk, O., Chen, G., Mathew, R., Jin, S., & White, E. (2007) · Genes & Development · doi:10.1101/gad.1565707 · Cited by 841 · 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
A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence
Kaplon, J., Zheng, L., Meissl, K., Chaneton, B., Selivanov, V. A., Mackay, G., van der Burg, S. H., Verdegaal, E. M. E., Cascante, M., Shlomi, T., et al. (2013) · Nature · doi:10.1038/nature12154 · Cited by 633 · see citing works
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells
Inami, Y., Waguri, S., Sakamoto, A., Kouno, T., Nakada, K., Hino, O., Watanabe, S., Ando, J., Iwadate, M., Yamamoto, M. P., et al. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201102031 · Cited by 602 · see citing works
Guo, J. Y., Karsli-Uzunbas, G., Mathew, R., Aisner, S. C., Kamphorst, J. J., Strohecker, A. M., Chen, G., Price, S., Lu, W., Teng, X., et al. (2013) · Genes & Development · doi:10.1101/gad.219642.113 · Cited by 589 · see citing works
Self-citationDankort, D. L., Filenova, E., Collado, M., Serrano, M., Jones, K. D., & McMahon, M. (2007) · Genes & Development · doi:10.1101/gad.1516407 · Cited by 476 · see citing works
Self-citationAutophagy facilitates glycolysis during Ras-mediated oncogenic transformation
Lock, R., Roy, S., Kenific, C. M., Su, J. S., Salas, E., Ronen, S. M., & Debnath, J. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-06-0500 · Cited by 467 · see citing works
Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesisPreprint
Wei, H., Wei, S., Gan, B., Xu, P., Zou, W., & Guan, J. (2011) · Genes & Development · doi:10.1101/gad.2051011 · Cited by 402 · see citing works
Role of autophagy in suppression of inflammation and cancer
White, E., Karp, C. M., Strohecker, A. M., Guo, Y., & Mathew, R. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.12.008 · Cited by 330 · see citing works
Self-citationBRAFV599EMutation Is the Leading Genetic Event in Adult Sporadic Papillary Thyroid Carcinomas
Puxeddu, E., Moretti, S., Elisei, R., Romei, C., Pascucci, R., Martinelli, M., Marino, C., Avenia, N., Rossi, E. D., Fadda, G., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031425 · Cited by 257 · see citing works
Assurance of mitochondrial integrity and mammalian longevity by the p62–Keap1–Nrf2–Nqo1 cascade
Kwon, J., Han, E., Bui, C., Shin, W., Lee, J. H., Lee, S., Choi, Y., Lee, A., Lee, K., Park, C., et al. (2012) · EMBO Reports · doi:10.1038/embor.2011.246 · Cited by 139 · see citing works
Huo, Y., Cai, H., Teplova, I., Bowman-Colin, C., Chen, G., Price, S. M., Barnard, N., Ganesan, S., Karantza, V., White, E., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0011 · Cited by 132 · see citing works
Self-citationLearning from oncocytic tumors: Why choose inefficient mitochondria?
Gasparre, G., Romeo, G. C., Rugolo, M., & Porcelli, A. M. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.08.006 · Cited by 125 · see citing works
Relevance of Mitochondrial Genetics and Metabolism in Cancer DevelopmentPreprint
Gasparre, G., Porcelli, A. M., Lenaz, G., & Romeo, G. C. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a011411 · Cited by 102 · see citing works
KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma
Li, Q. K., Singh, A., Biswal, S., Askin, F., & Gabrielson, E. (2011) · Journal of Human Genetics · doi:10.1038/jhg.2010.172 · Cited by 90 · see citing works
Iommarini, L., Calvaruso, M. A., Kurelac, I., Gasparre, G., & Porcelli, A. M. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.05.016 · Cited by 66 · see citing works
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Levy, J. M. M., Towers, C. G., & Thorburn, A. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.53 · Cited by 2,526 · 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
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Rojo de la Vega, M., Chapman, E., & Zhang, D. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.022 · Cited by 1,672 · see citing works
Autophagy in major human diseases
Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108863 · Cited by 1,585 · see citing works
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White, E. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73941 · Cited by 1,332 · see citing works
Self-citationAutophagy in malignant transformation and cancer progression
Galluzzi, L., Pietrocola, F., Bravo‐San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D. A., Karantza, V., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490784 · Cited by 1,182 · see citing works
Mizushima, N., & Levine, B. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2022774 · Cited by 1,140 · see citing works
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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
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Galluzzi, L., Pietrocola, F., Levine, B., & Kroemer, G. (2014) · Cell · doi:10.1016/j.cell.2014.11.006 · Cited by 855 · see citing works
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“However, at later stages of tumorigenesis, loss of autophagy leads to metabolic crisis resulting in defective mitochondria, reduced tumor growth and the conversion of adenomas and adenocarcinomas to oncocytomas [96].”
Background
- Authors
- Strohecker, A. M., Guo, J. Y., Karsli-Uzunbas, G., Price, S. M., Chen, G. J., Mathew, R., McMahon, M., & White, E.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- White, Eileen
- Venue
- Cancer Discovery
- Published
- 2013-11-01
- Volume
- 3
- Issue
- 11
- Pages
- 1272-1285
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3823822
- OpenAlex
- W2125231982
- Cited by
- 435
- References
- 36
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 21 · 2023: 27 · 2022: 39 · 2021: 56 · 2020: 38 · 2019: 41 · 2018: 33 · 2017: 30 · 2016: 39 · 2015: 36 · 2014: 30 · 2013: 5
- FWCI
- 26.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Association for Cancer Research
- Rutgers Cancer Institute of New Jersey
- University of California, San Francisco
- National Cancer Institute (R37CA053370, R37-CA53370, RCI CA147961, RC1CA147961, CA131261, R01CA130893, P30CA072720, R01CA131261, R01CA163591)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- autophagy, ATG7, BRAF V600E mutation, lung cancer, oxidative stress, Nrf2, Trp53, tumor growth, glutamine addiction, autophagy inhibition, tumor suppressor function
- MeSH terms
- Autophagy-Related Protein 7, Adenocarcinoma, Adenoma, Animals, Autophagy, Cell Transformation, Neoplastic, Disease Models, Animal, Glutamine, Humans, Lung Neoplasms, Microtubule-Associated Proteins, Mitochondria, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Gene Deletion, Adenoma, Oxyphilic, Oxidative Stress, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, NF-E2-Related Factor 2, Mice
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