Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients - PubMed (original) (raw)

Review

Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients

Jean M Mulcahy Levy et al. Cell Death Differ. 2020 Mar.

Abstract

Autophagy allows for cellular material to be delivered to lysosomes for degradation resulting in basal or stress-induced turnover of cell components that provide energy and macromolecular precursors. These activities are thought to be particularly important in cancer where both tumor-promoting and tumor-inhibiting functions of autophagy have been described. Autophagy has also been intricately linked to apoptosis and programmed cell death, and understanding these interactions is becoming increasingly important in improving cancer therapy and patient outcomes. In this review, we consider how recent discoveries about how autophagy manipulation elicits its effects on cancer cell behavior can be leveraged to improve therapeutic responses.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1

Fig. 1. Clinical and pre-clinical targets of inhibition along the five stages of autophagy.

The process of autophagy is divided into five distinct stages: initiation, nucleation, expansion and elongation, closure and fusion, and cargo degradation. Each stage has potential clinical targets. The ULK/FIP200/ATG13 complex induces vesicle nucleation, which continues with involvement of the BECN1 complex which includes VPS34. Multiple ULK1 and VPS34 inhibitors are in pre-clinical evaluation. Expansion and elongation are mediated by ubiquitin-like conjugation systems with conjugation of phosphatidylethanolamine (PE) to LC3-II facilitated by the protease, ATG4B, and the E1-like enzyme, ATG7, resulting in LC3-II incorporation into the growing membrane. Multiple ATG4B inhibitors are in pre-clinical development. Finally, fusion of the autophagosome and lysosome as well as degradation of intravesicular products can be inhibited through the use of lysosomal targeted agents such as CQ and HCQ, which are already in clinical use and under investigation in clinical trials. Additionally, more potent drugs are in preclinical development that target the lysosome and the lysosomal enzyme PPT1.

Fig. 2

Fig. 2. The interplay between autophagy and apoptosis.

Autophagy and apoptosis interact through the control of multiple proteins. BH3-only proteins disrupt the interaction of Bcl-2 and Beclin 1. This allows Beclin 1 to stimulate autophagy through Vps34 and Bcl-2 to inhibit apoptosis through interaction with Bax/Bax. Autophagy controls cellular levels of FOXO3. Increased FOXO3 stimulates autophagy regulation genes to induce autophagy and reduce overall FOXO3 levels. If there is continued presence of elevated FOXO3, it results in increased transcription of PUMA, which is then free to block with interaction between Bcl-2 and Bax/Bak. Once Bax/Bak are released, they can permeabilize mitochondria resulting in effector caspase activation and apoptotic cell death.

References

    1. Assembly TN. The Nobel Assembly at Karolinska Instiutet has today decided to award the 2016 Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi. 2016. https://www.nobelprize.org/nobel_prizes/medicine/laureates/2016/press.html. Accessed 25 May 2017.
    1. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401–10. - PMC - PubMed
    1. Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M, Nitsch R, et al. A dual role for autophagy in a murine model of lung cancer. Nat Commun. 2014;5:3056. - PubMed
    1. Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30:1913–30. - PMC - PubMed
    1. Galluzzi Lorenzo, Pietrocola Federico, Bravo‐San Pedro José Manuel, Amaravadi Ravi K, Baehrecke Eric H, Cecconi Francesco, Codogno Patrice, Debnath Jayanta, Gewirtz David A, Karantza Vassiliki, Kimmelman Alec, Kumar Sharad, Levine Beth, Maiuri Maria Chiara, Martin Seamus J, Penninger Josef, Piacentini Mauro, Rubinsztein David C, Simon Hans‐Uwe, Simonsen Anne, Thorburn Andrew M, Velasco Guillermo, Ryan Kevin M, Kroemer Guido. Autophagy in malignant transformation and cancer progression. The EMBO Journal. 2015;34(7):856–880. - PMC - PubMed

Publication types

MeSH terms

Grants and funding

LinkOut - more resources