Format

Send to

Choose Destination
Cell Metab. 2019 Feb 5;29(2):285-302.e7. doi: 10.1016/j.cmet.2018.10.005. Epub 2018 Nov 8.

Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models.

Author information

1
Molecular and Cell Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, San Diego, CA, USA.
2
Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, San Diego, CA, USA.
3
Molecular and Cell Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, San Diego, CA, USA. Electronic address: shaw@salk.edu.
4
Molecular and Cell Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, San Diego, CA, USA. Electronic address: rsvensson@salk.edu.

Abstract

AMPK, a conserved sensor of low cellular energy, can either repress or promote tumor growth depending on the context. However, no studies have examined AMPK function in autochthonous genetic mouse models of epithelial cancer. Here, we examine the role of AMPK in murine KrasG12D-mediated non-small-cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor-the predominant upstream activating kinase of AMPK and 12 related kinases. Unlike LKB1 deletion, AMPK deletion in KrasG12D lung tumors did not accelerate lung tumor growth. Moreover, deletion of AMPK in KrasG12D p53f/f tumors reduced lung tumor burden. We identified a critical role for AMPK in regulating lysosomal gene expression through the Tfe3 transcription factor, which was required to support NSCLC growth. Thus, AMPK supports the growth of KrasG12D-dependent lung cancer through the induction of lysosomes, highlighting an unrecognized liability of NSCLC.

KEYWORDS:

AMPK; Kras; LKB1; Tfe3; Tfeb; cancer; lung; lysosomes; metabolism; tumor

PMID:
30415923
PMCID:
PMC6365213
[Available on 2020-02-05]
DOI:
10.1016/j.cmet.2018.10.005

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center