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Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition.


ABSTRACT: While autophagy is thought to be an essential process in some cancer cells, it is unknown if or how such cancer cells can circumvent autophagy inhibition. To address this, we developed a CRISPR/Cas9 assay with dynamic live-cell imaging to measure acute effects of knockout (KO) of autophagy genes compared to known essential and non-essential genes. In some cancer cells, autophagy is as essential for cancer cell growth as mRNA transcription or translation or DNA replication. However, even these highly autophagy-dependent cancer cells evolve to circumvent loss of autophagy by upregulating NRF2, which is necessary and sufficient for autophagy-dependent cells to circumvent ATG7 KO and maintain protein homeostasis. Importantly, however, this adaptation increases susceptibly to proteasome inhibitors. These studies identify a common mechanism of acquired resistance to autophagy inhibition and show that selection to avoid tumor cell dependency on autophagy creates new, potentially actionable cancer cell susceptibilities.

SUBMITTER: Towers CG 

PROVIDER: S-EPMC7233142 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition.

Towers Christina G CG   Fitzwalter Brent E BE   Regan Daniel D   Goodspeed Andrew A   Morgan Michael J MJ   Liu Chang-Wei CW   Gustafson Daniel L DL   Thorburn Andrew A  

Developmental cell 20190801 6


While autophagy is thought to be an essential process in some cancer cells, it is unknown if or how such cancer cells can circumvent autophagy inhibition. To address this, we developed a CRISPR/Cas9 assay with dynamic live-cell imaging to measure acute effects of knockout (KO) of autophagy genes compared to known essential and non-essential genes. In some cancer cells, autophagy is as essential for cancer cell growth as mRNA transcription or translation or DNA replication. However, even these hi  ...[more]

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