Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover

Publication date: 12 March 2018
Source:Developmental Cell, Volume 44, Issue 5
Author(s): Brent E. Fitzwalter, Christina G. Towers, Kelly D. Sullivan, Zdenek Andrysik, Maria Hoh, Michael Ludwig, Jim O'Prey, Kevin M. Ryan, Joaquin M. Espinosa, Michael J. Morgan, Andrew Thorburn
Macroautophagy (autophagy) is intimately linked with cell death and allows cells to evade apoptosis. This has prompted clinical trials to combine autophagy inhibitors with other drugs with the aim of increasing the likelihood of cancer cells dying. However, the molecular basis for such effects is unknown. Here, we describe a transcriptional mechanism that connects autophagy to apoptosis. The autophagy-regulating transcription factor, FOXO3a, is itself turned over by basal autophagy creating a potential feedback loop. Increased FOXO3a upon autophagy inhibition stimulates transcription of the pro-apoptotic BBC3/PUMA gene to cause apoptosis sensitization. This mechanism explains how autophagy inhibition can sensitize tumor cells to chemotherapy drugs and allows an autophagy inhibitor to change the action of an MDM2-targeted drug from growth inhibition to apoptosis, reducing tumor burden in vivo. Thus, a link between two processes mediated via a single transcription factor binding site in the genome can be leveraged to improve anti-cancer therapies.

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Teaser

Fitzwalter et al. uncover a link between autophagy and apoptosis, explaining how autophagy inhibitors can improve anti-cancer drugs by increasing sensitivity to apoptosis. The transcription factor FOXO3a, an autophagy regulator, is itself degraded by basal autophagy. Disruption of autophagy allows FOXO3a to upregulate BBC3/PUMA expression and thus cause apoptosis sensitization.


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