CommentaryAutophagy as a mediator of chemotherapy-induced cell death in cancer
Graphical abstract
Section snippets
Autophagy: an introduction
Autophagy is a self-degradative process that enables cells to cope with stresses such as nutrient deprivation, ER stress, pathogen infection or hypoxia. Autophagy is thus generally considered to be a survival mechanism. On the other hand, when the severity or the duration of the stress is too long, or in apoptotic-deficient cells, autophagy may participate in cell death. Therefore, it has been called type II programmed cell death (type I being apoptosis itself). The role of autophagy in cell
Role of autophagy in cancer
Alterations in the autophagy pathway in cancer cells raised a paradox because autophagy functions as a tumor suppressive mechanism, but is also used by cancer cells for cytoprotection to cope with their hostile microenvironment [13], [14], [15]. This dual role of autophagy in tumor development is illustrated by the fact that colorectal cancer patients with extensive over- or underexpression of Beclin-1 have a much poorer overall survival [16].
Balance between apoptosis and autophagy for inducing cell death
In their revised version of the hallmarks of cancer, Hanahan and Weinberg added other types of cell death beyond the previously described apoptosis. In this regard, autophagy as well as necrosis is seen as contributing to and/or counteracting drug-induced apoptosis and cell death [37]. Complex crosstalk between apoptosis and autophagy has been unraveled. There is substantial evidence indicating that suppression of apoptosis induces autophagy, while autophagy inhibition causes apoptosis [38],
To provoke cell death
As described above, half of the studies show that autophagy is required for the efficient killing of tumor cells when treated with anticancer therapies. In line with these observations, researchers are working to design new drugs that would induce autophagy by themselves, and hence eliminate cancer cells [73]. Among the potential targets in autophagy, the Akt-mTOR pathway is the most investigated one. Indeed, proteins Akt, PTEN (phosphatase and tensin homolog) and mTOR, as well as some of the
Conclusion
The involvement of autophagy in chemotherapeutic agent-induced cell death is very complex. On one hand, autophagy may protect from apoptosis and hence, autophagy inhibitors have potential use as drugs to overcome anticancer therapy resistance. On the other hand, this process participates in cell death in certain circumstances. In that case, its induction may help to eradicate malignant cells. In order to reach clinical application, we must first better understand the factors that influence the
Acknowledgments
Annick Notte is a Research Fellow at FNRS (Fonds de la Recherche Scientifique, Belgium) and Lionel Leclere is a recipient of a FRIA grant (Fonds de la Recherche Scientifique, Belgium). This article presents results of the Belgian Program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. The responsibility is assumed by its authors.
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