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Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition

54 Pages Posted: 19 Mar 2019 Publication Status: Published

See all articles by Christina G. Towers

Christina G. Towers

University of Colorado at Denver - Department of Pharmacology

Brent E. Fitzwalter

University of Colorado at Denver - Department of Pharmacology

Daniel Regan

Colorado State University, Fort Collins - Flint Animal Cancer Center

Michael J. Morgan

University of Colorado at Denver - Department of Pharmacology

Chang-wei Liu

University of Colorado at Denver - Department of Biochemistry and Molecular Genetics

Daniel L. Gustafson

Colorado State University, Fort Collins - Flint Animal Cancer Center

Andrew Thorburn

University of Colorado at Denver - Department of Pharmacology

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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 but this 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.

Keywords: Autophagy, CRISPR/Cas9, NRF2, Chloroquine resistance, Proteasomal Degradation

Suggested Citation

Towers, Christina G. and Fitzwalter, Brent E. and Regan, Daniel and Morgan, Michael J. and Liu, Chang-wei and Gustafson, Daniel L. and Thorburn, Andrew, Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition (March 19, 2019). Available at SSRN: https://ssrn.com/abstract=3353707 or http://dx.doi.org/10.2139/ssrn.3353707
This version of the paper has not been formally peer reviewed.

Christina G. Towers

University of Colorado at Denver - Department of Pharmacology

Box 173364
1250 14th Street
Denver, CO 80217
United States

Brent E. Fitzwalter

University of Colorado at Denver - Department of Pharmacology

Box 173364
1250 14th Street
Denver, CO 80217
United States

Daniel Regan

Colorado State University, Fort Collins - Flint Animal Cancer Center

Fort Collins, CO 80523-1771
United States

Michael J. Morgan

University of Colorado at Denver - Department of Pharmacology

Box 173364
1250 14th Street
Denver, CO 80217
United States

Chang-wei Liu

University of Colorado at Denver - Department of Biochemistry and Molecular Genetics

Building 500 - 13001 E. 17th Place, Campus Box C29
Aurora, CO 80045
United States

Daniel L. Gustafson

Colorado State University, Fort Collins - Flint Animal Cancer Center

Fort Collins, CO 80523-1771
United States

Andrew Thorburn (Contact Author)

University of Colorado at Denver - Department of Pharmacology ( email )

Box 173364
1250 14th Street
Denver, CO 80217
United States

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