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Autophagy Function and Dysfunction: Potential Drugs as Anti-Cancer Therapy


Autophagy Function and Dysfunction: Potential Drugs as Anti-Cancer Therapy

Francesca Cuomo et al. Cancers (Basel).


Autophagy is a highly conserved catabolic and energy-generating process that facilitates the degradation of damaged organelles or intracellular components, providing cells with components for the synthesis of new ones. Autophagy acts as a quality control system, and has a pro-survival role. The imbalance of this process is associated with apoptosis, which is a "positive" and desired biological choice in some circumstances. Autophagy dysfunction is associated with several diseases, including neurodegenerative disorders, cardiomyopathy, diabetes, liver disease, autoimmune diseases, and cancer. Here, we provide an overview of the regulatory mechanisms underlying autophagy, with a particular focus on cancer and the autophagy-targeting drugs currently approved for use in the treatment of solid and non-solid malignancies.

Keywords: apoptosis; autophagy; cancer; chloroquine; drugs; mTOR inhibitors.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Schematic representation of regulatory pathways involved in the autophagic event and point of inhibition/activation. Under a deprivation of nutrients or growth factors, ULK activation occurs via the activation of activating AMP kinase (AMPK) and/or the inhibition of mTOR. ULK functions in a complex with FIP200 and Atg13, which phosphorylates Beclin-1, leading to VPS34 activation and phagophore formation. Association between Beclin-1 and Bcl-2 inhibits autophagy. Two ubiquitin-like conjugation systems are engaged, one involving Atg12, Atg5, and Atg16L proteins, and the other converting LC3 protein from its LC3I form to LC3II. This event leads to closure of an elongated phagophore with the formation of a mature autophagosome, which is followed by transport of the autophagic cargo to lysosomes, degradation of this cargo by lysosomal hydrolases, and recycling of the products for use in metabolism.
Figure 2
Figure 2
Schematic representation of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 pathways and point of inhibition. mTORC1 associates with endosomal and lysosomal membranes via its effector, mTORC2. Once phosphorylated, AKT can activate mTORC1 directly, either by phosphorylating and dissociating the proline-rich Akt substrate of 40kDa (PRAS40) from the regulatory-associated protein of mTOR (RAPTOR) or by inhibiting tuberous sclerosis (TSC)1/2 complex formation, releasing the Ras homolog enriched in brain (RHEB), which is an activator of mTORC1. Protein translation and the synthesis of nucleotide lipid via 4E-BP1 and S6K1 is regulated by mTORC1. In tumorigenesis, mTORC2 activates signal transducer and activator transcription (STAT3), hypoxia-inducible factor 1a (HIF1a), and protein phosphatase 2A (PP2A). In addition, mTORC2 regulates serum glucose kinase (SGK) and protein kinase (PKC) to induce cell survival, cytoskeleton organization, and cell migration. mTORC1 functions as a negative regulator of autophagy, exerting its inhibitory action by phosphorylating and inactivating ULK1/2 and Atg13.

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