Autophagy is required for glucose homeostasis and lung tumor maintenance

Gizem Karsli-Uzunbas, Jessie Yanxiang Guo, Sandy Price, Xin Teng, Saurabh V. Laddha, Sinan Khor, Nada Y. Kalaany, Tyler Jacks, Chang S. Chan, Joshua D. Rabinowitz, Eileen White

Research output: Contribution to journalArticle

232 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)915-927
Number of pages13
JournalCancer Discovery
Volume4
Issue number8
DOIs
StatePublished - Aug 2014

All Science Journal Classification (ASJC) codes

  • Oncology

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    Karsli-Uzunbas, G., Guo, J. Y., Price, S., Teng, X., Laddha, S. V., Khor, S., Kalaany, N. Y., Jacks, T., Chan, C. S., Rabinowitz, J. D., & White, E. (2014). Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discovery, 4(8), 915-927. https://doi.org/10.1158/2159-8290.CD-14-0363