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Review
. 2023 Jun 9:11:1177440.
doi: 10.3389/fcell.2023.1177440. eCollection 2023.

Inhibition of autophagy; an opportunity for the treatment of cancer resistance

Asha Tonkin-Reeves  1 , Charlett M Giuliani  2   3 , John T Price  1   2   3   4
Affiliations
Review

Inhibition of autophagy; an opportunity for the treatment of cancer resistance

Asha Tonkin-Reeves et al. Front Cell Dev Biol. .

Abstract

The process of macroautophagy plays a pivotal role in the degradation of long-lived, superfluous, and damaged proteins and organelles, which are later recycled for cellular use. Normal cells rely on autophagy to combat various stressors and insults to ensure survival. However, autophagy is often upregulated in cancer cells, promoting a more aggressive phenotype that allows mutated cells to evade death after exposure to therapeutic treatments. As a result, autophagy has emerged as a significant factor in therapeutic resistance across many cancer types, with underlying mechanisms such as DNA damage, cell cycle arrest, and immune evasion. This review provides a comprehensive summary of the role of autophagy in therapeutic resistance and the limitations of available autophagic inhibitors in cancer treatment. It also highlights the urgent need to explore new inhibitors that can synergize with existing therapies to achieve better patient treatment outcomes. Advancing research in this field is crucial for developing more effective treatments that can help improve the lives of cancer patients.

Keywords: autophagy; autophagy mechanisms; cancer; drug resisitance; therapeutic resistance.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Mammalian macroautophagy and autophagy modulators. Autophagosome formation occurs when mTOR and other signalling pathways activate the ULK1 complex. Subsequently, the phagophore is elongated by stimulating the Atg5-Atg12-Atg16 complex. This process continues onto the maturation of the autophagosome with the ubiquitin-like reaction, which converts LC3-I to LC3-II. After this, the mature autophagosome fuses with the lysosome to form the autolysosome, which utilises enzymes to degrade proteins and organelles encapsulated by the autophagosome. The resulting material is recycled. Created with BioRender.com.
FIGURE 2
FIGURE 2
Autophagy regulation. Autophagy initiation is stimulated in response to nutritional stress, genotoxic stress, and various other stresses. A prominent player in autophagy regulation is the mTOR pathway and mTORC1. Once activated, mTORC1 stimulates the ULK1 complex and the downstream signalling cascade results in autophagy formation. The mTORC1 complex is stimulated by several upstream targets, including the PTEN/PI3K/Akt axis, amino acids, and AMPK. In addition, AMPK can also directly stimulate ULK1 and Beclin 1, leading to autophagosome formation. Created with BioRender.com.
FIGURE 3
FIGURE 3
Increased autophagy prevents cancer cell elimination and contributes to therapeutic resistance. Autophagy is upregulated in cancer cells due to various microenvironmental stresses including exposure to therapeutics. Autophagy eliminates MHC-I and decreases antigen presentation and CD8+ T cells which inhibits NK- and CTL-mediated cell lysis and the thus the immune response. Apoptotic cell death is also reduced as autophagy facilitates mitochondria and cleaved caspase-8 degradation which prevents downstream signalling cascades. It also prevents death signalling cascades by actively promoting DNA damage repair. The mechanism behind this is unclear. Potentially, autophagy’s degradation of Cyclin D1 and thus cell cycle arrest allows for this. Its upregulation also prevents the Ferroptosis, Pyroptosis and LMP-associated death pathways through unclear mechanisms. Suppression of autophagy via inhibitors could prevent the degradation of components that would otherwise inhibit cell death pathways. Created with BioRender.com.
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