Autophagy modulates lipid metabolism to maintain metabolic flexibility for <i>Lkb1</i>-deficient <i>Kras</i>-driven lung tumorigenesis

Bhatt, Vrushank; Khayati, Khoosheh; Hu, Zhixian; Lee, Amy; Kamran, Wali; Su, Xiaoyang; Guo, Jessie Yanxiang

doi:10.1101/gad.320481.118

Cited by 96 publications

(88 citation statements)

References 56 publications

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“…Importantly, the extent of tumor growth inhibition by autophagy inhibition was more pronounced in KL tumors than in Kras -mutant; Trp53 -mutant (KP) tumors. These fi ndings strongly suggest that autophagy inhibition could be an effective therapeutic strategy specifically for treating KL lung cancer ( 120 ).…”

Section: Lkb1 -Mutant Cancersmentioning

confidence: 87%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specifi c autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Signifi cance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefi t from this approach.

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Section: Lkb1 -Mutant Cancersmentioning

confidence: 87%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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“…Moreover, AMPK and autophagy were activated in Lkb1-deficient lung tumors (19,20). p53 is activated upon autophagy deletion, leading to increased apoptotic rates in mouse liver and brain, impairing the overall mouse homeostasis (36).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Compensates for Lkb1 Loss to Maintain Adult Mice Homeostasis and Survival

Guo

Khayati

Bhatt

et al. 2020

Preprint

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Liver Kinase B1 (LKB1) is the major energy sensor for cells to respond to metabolic stress. Autophagy degrades and recycles proteins, macromolecules, and organelles for cells to survive starvation. To access the role and cross-talk between autophagy and Lkb1 in normal tissue homeostasis, we generated genetically engineered mouse models where we can conditionally delete Lkb1 and autophagy essential gene, Atg7, respectively or simultaneously, throughout the adult mice. We found that Lkb1 was essential for the survival of adult mice, and autophagy activation could temporarily compensate for the acute loss of Lkb1 and extend mouse life span. We further found that acute deletion of Lkb1 in adult mice led to impaired intestinal barrier function, hypoglycemia, and abnormal serum metabolism, which was partly rescued by the Lkb1 loss-induced autophagy upregulation via inhibiting p53 induction. Taken together, we demonstrated that autophagy and Lkb1 work synergistically to maintain adult mouse homeostasis and survival.

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“…The role of autophagy in cancer is somewhat paradoxical; in some cases, autophagy can help to remove cancer cells, whereas in other cases tumor cells can harness autophagy as a protective process during nutrient deprivation, oxidative stress, and other stress-inducing factors [ 119 , 120 , 121 ]. The autophagy adaptor sequestome 1 (p62) can promote NRF2 activation via competitive binding to KEAP1 to increase the free NRF2 pool [ 122 ] and also by promoting autophagic degradation of KEAP1 [ 123 ].…”

Section: Metabolic Pathways That Stabilize Nrf2mentioning

confidence: 99%

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

DeBlasi

DeNicola

2020

Cancers

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The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.

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Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis

Cited by 96 publications

References 56 publications

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Autophagy Compensates for Lkb1 Loss to Maintain Adult Mice Homeostasis and Survival

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

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