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

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiation and tumor growth. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors.

Original languageEnglish (US)
Pages (from-to)150-165
Number of pages16
JournalGenes and Development
Volume33
Issue number3-4
DOIs
StatePublished - Feb 1 2019

Fingerprint

Autophagy
Lipid Metabolism
Carcinogenesis
Lung
Neoplasms
Phosphotransferases
Liver
Essential Genes
Recycling
Lung Neoplasms
Homeostasis
Fatty Acids
Cell Proliferation
Lipids
Amino Acids
Food
Growth

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • Autophagy
  • Energy metabolism
  • LKB1
  • Lipid metabolism
  • Non-small cell lung cancer

Cite this

Bhatt, Vrushank ; Khayati, Khoosheh ; Hu, Zhixian Sherrie ; Lee, Amy ; Kamran, Wali ; Su, Xiaoyang ; Guo, Yanxiang. / Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient kras-driven lung tumorigenesis. In: Genes and Development. 2019 ; Vol. 33, No. 3-4. pp. 150-165.
@article{0167dd53550943688b6a4660894752d0,
title = "Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient kras-driven lung tumorigenesis",
abstract = "Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiation and tumor growth. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors.",
keywords = "Autophagy, Energy metabolism, LKB1, Lipid metabolism, Non-small cell lung cancer",
author = "Vrushank Bhatt and Khoosheh Khayati and Hu, {Zhixian Sherrie} and Amy Lee and Wali Kamran and Xiaoyang Su and Yanxiang Guo",
year = "2019",
month = "2",
day = "1",
doi = "10.1101/gad.320481.118",
language = "English (US)",
volume = "33",
pages = "150--165",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "3-4",

}

Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient kras-driven lung tumorigenesis. / Bhatt, Vrushank; Khayati, Khoosheh; Hu, Zhixian Sherrie; Lee, Amy; Kamran, Wali; Su, Xiaoyang; Guo, Yanxiang.

In: Genes and Development, Vol. 33, No. 3-4, 01.02.2019, p. 150-165.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient kras-driven lung tumorigenesis

AU - Bhatt, Vrushank

AU - Khayati, Khoosheh

AU - Hu, Zhixian Sherrie

AU - Lee, Amy

AU - Kamran, Wali

AU - Su, Xiaoyang

AU - Guo, Yanxiang

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiation and tumor growth. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors.

AB - Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiation and tumor growth. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors.

KW - Autophagy

KW - Energy metabolism

KW - LKB1

KW - Lipid metabolism

KW - Non-small cell lung cancer

UR - http://www.scopus.com/inward/record.url?scp=85060905564&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060905564&partnerID=8YFLogxK

U2 - 10.1101/gad.320481.118

DO - 10.1101/gad.320481.118

M3 - Article

C2 - 30692209

AN - SCOPUS:85060905564

VL - 33

SP - 150

EP - 165

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 3-4

ER -