Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences
Autophagy is a catabolic process whose activation may help cancer cells to adapt to cellular stress although, in some instances, it can induce cell death. Autophagy stimulation or inhibition has been considered an opportunity to treat cancer, especially in combination with anticancer therapies, although autophagy manipulation may be viewed as controversial. Thus, whether to induce or to inhibit autophagy may be the best option in the different cancer patients is still matter of debate. Her we will recapitulate the possible advantages or disadvantages of manipulating autophagy in cancer, not only with the aim to obtain cancer cell death and disable oncogenes, but also to evaluate its interplay with the immune response which is fundamental for the success of anticancer therapies.
KeywordsAutophagy Cancer Immunogenic cell death (ICD) Endoplasmic reticulum (ER stress) Unfolded protein response (UPR) Chloroquine (CQ) Hydroxichloroquine (HCQ) p53 HSF1 NRF2
Autophagy related 5
C/EBP homologous protein
Damage Associated Molecular Patterns
Eukaryotic translation initiation factor 2α
Hypoxia Inducible Factor-1
Heat Shock Factor 1
Heat shock protein 90
Immunogenic dell death
kelch like ECH associated protein 1
Kaposi’s sarcoma-associated herpesvirus
myeloid suppressive DCs
Mammalian target of rapamycin
Nuclear factor erytroid 2 like
Reactive oxygen species
Unfolded protein response
X-box binding protein 1
Macroautophagy, hereafter referred as autophagy, is a bulk degradative process up-regulated under stressful conditions, playing a central role in cellular homeostasis . Autophagy usually helps cancer cells to cope with the shortage of nutrients and with the hypoxic conditions in which they are forced to survive. The modulation of autophagy may play dual roles in tumor suppression and promotion [2, 3]. Its induction is generally considered a valid option in cancer prevention , particularly because through a selective form of autophagy, that is the mitophagy, cells ride out of damaged mitochondria, the main producers of reactive oxygen species (ROS) that cause DNA mutations . Autophagy modulators have been used as new anticancer strategy [3, 6], although how to manipulate autophagy to improve the treatment of established cancers is still not clear. Recently, a role of autophagy in the regulation the function of the cells present in the tumor microenvironment such as cancer-associated fibroblasts and immune cells has been highlighted, making the issue of autophagy manipulation even more challenging [7, 8]. Even if many reviews have been published in the last years about autophagy and cancer, here, we will try to recapitulate the multifaceted role of autophagy in cancer therapy and how its manipulation may impact immune response that plays an essential role in tumor regression.
Interplay between autophagy and immune system in anticancer therapies
Despite the unclear role of autophagy inhibition in improving the outcome of chemotherapies, clinical trials have started to use CQ or HCQ, mainly in combination with chemotherapies, to treat cancer patients [9, 31, 32]. The results so far obtained have been quite disappointing and the treatment failure may be explained also by the reduction of autophagy-induced ATP release, and by the fact that these anti-malaric drugs inhibit lysosomal acidification, thus may affect many other important cellular processes other than autophagy . Moreover, when systemically administrated, CQ or HCQ may have several side effects  and act on immune cells suppressing their functions, i.e. stimulating the T regulatory cells (Treg) , altering class II antigen presentation or cross-presentation by DCs  or even impairing DC formation, all mechanisms inducing suppression of the immune response . Interestingly, the reduction of autophagy in monocytes represents a strategy through which the human oncogenic gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) alter monocyte differentiation into DCs, to escape from immune recognition, as also demonstrated by our studies [38, 39, 40]. In line with the evidences indicating that autophagy is required for an effective immune response and for the activation of immune system in the course of anticancer chemotherapies, we have found that autophagy inhibitor CQ abrogates the cytotoxic effect of curcumin against breast cancer in immune competent mice while increases it in immune deficient mice . These findings point out, once again, that autophagy inhibition reduces the success of anticancer therapy in the presence of a functional immune system. Moreover, this study evidenced that CQ counteracts the curcumin down-regulation of Hypoxia Inducing Factor (HIF)-1, the main effector of cellular response to hypoxia involved in cancer progression and chemoresistance , and that sustained HIF-1 activation correlates with higher infiltrate of immune suppressive Treg cells in the tumor bed of curcumin plus CQ-treated mice . In agreement, previous studies have shown that HIF-1 could be degraded through the lysosomal route [42, 43], suggesting that autophagy inhibition by CQ may interfere with HIF-1 degradation promoted by curcumin and sustain its oncogenic function for tumor progression.
Autophagy and oncogenes degradation
Interplay between autophagy, endoplasmic reticulum (ER) stress and unfolded protein response (UPR)
Based on the findings reported by the majority of studies in this field, it seems that autophagy induction rather than autophagy inhibition could be exploited to improve the outcome of cancer treatment, at least in immune competent hosts. Therefore, nutraceuticals, exercise, calory restriction or calory restriction mimetics (such as metformin), all able to induce autophagy, are being considered as a possible alternative avenue to treat cancer in combination with chemotherapies [87, 88]. In addition, just to make this complicated field more complicated, it is emerging that inhibiting autophagy specifically in cancer cells may enhances the abscopal response to radiation therapy, that is, the ability of localized radiation to trigger systemic antitumor effects [89, 90]. thus suggesting that selective autophagy inhibition in cancer cells and systemic induction of autophagy could be combined to improve the outcome of anti-cancer therapy. Considering the role of autophagy in regulating the expression of oncogenes and modulating the function of the cells of the tumor environment such as fibroblasts and immune cells, more questions than answers have been raised by this review. Therefore, more investigations are needed to further clarify the possible consequences of autophagy manipulation in cancer therapy.
We thank all the people in the lab for critical discussion.
Conception and design: MC, GD; Writing: MC, GD; revision of the manuscript: MSGM, MG, AG, AF. All authors read and approved the final manuscript.
The research in M.C.’s lab within the realm of this manuscript is funded by Istituto Pasteur Italia Fondazione Cenci Bolognetti and by Fondi Ateneo; in G.D.’ lab is funded by AIRC and by Fondi Ateneo.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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