Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2015
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| Online Access: | http://hdl.handle.net/1721.1/96526 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1826208366206124032 |
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| author | Karsli-Uzunbas, Gizem Guo, Jessie Yanxiang Price, Sandy Teng, Xin Laddha, Saurabh V. Khor, Sinan Kalaany, Nada Y. Chan, Chang S. Rabinowitz, Joshua D. White, Eileen Jacks, Tyler E |
| author2 | MIT Kavli Institute for Astrophysics and Space Research |
| author_facet | MIT Kavli Institute for Astrophysics and Space Research Karsli-Uzunbas, Gizem Guo, Jessie Yanxiang Price, Sandy Teng, Xin Laddha, Saurabh V. Khor, Sinan Kalaany, Nada Y. Chan, Chang S. Rabinowitz, Joshua D. White, Eileen Jacks, Tyler E |
| author_sort | Karsli-Uzunbas, Gizem |
| collection | MIT |
| description | Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer.
Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers. |
| first_indexed | 2024-09-23T14:04:38Z |
| format | Article |
| id | mit-1721.1/96526 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:04:38Z |
| publishDate | 2015 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/965262022-09-28T18:11:35Z Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance Karsli-Uzunbas, Gizem Guo, Jessie Yanxiang Price, Sandy Teng, Xin Laddha, Saurabh V. Khor, Sinan Kalaany, Nada Y. Chan, Chang S. Rabinowitz, Joshua D. White, Eileen Jacks, Tyler E MIT Kavli Institute for Astrophysics and Space Research Jacks, Tyler E. Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers. Val Skinner Foundation National Institutes of Health (U.S.) (RC1 CA147961) Rutgers Cancer Institute of New Jersey Rutgers Cancer Institute of New Jersey (P30 CA072720) National Institutes of Health (U.S.) (R01 CA163591) National Institutes of Health (U.S.) (R37 CA53370) National Institutes of Health (U.S.) (R01 CA130893) 2015-04-10T18:47:30Z 2015-04-10T18:47:30Z 2014-05 2014-05 Article http://purl.org/eprint/type/JournalArticle 2159-8274 2159-8290 http://hdl.handle.net/1721.1/96526 Karsli-Uzunbas, G., J. Y. Guo, S. Price, X. Teng, S. V. Laddha, S. Khor, N. Y. Kalaany, et al. “Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance.” Cancer Discovery 4, no. 8 (May 29, 2014): 914–927. https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1158/2159-8290.cd-14-0363 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research PMC |
| spellingShingle | Karsli-Uzunbas, Gizem Guo, Jessie Yanxiang Price, Sandy Teng, Xin Laddha, Saurabh V. Khor, Sinan Kalaany, Nada Y. Chan, Chang S. Rabinowitz, Joshua D. White, Eileen Jacks, Tyler E Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance |
| title | Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance |
| title_full | Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance |
| title_fullStr | Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance |
| title_full_unstemmed | Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance |
| title_short | Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance |
| title_sort | autophagy is required for glucose homeostasis and lung tumor maintenance |
| url | http://hdl.handle.net/1721.1/96526 https://orcid.org/0000-0001-5785-8911 |
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