Autophagy in cancer biology and therapy

doi:10.1007/s11515-014-1294-2

Front. Biol.

2014, Vol. 9

Issue (1) : 35-50 https://doi.org/10.1007/s11515-014-1294-2

REVIEW

Autophagy in cancer biology and therapy

Noor GAMMOH,Simon WILKINSON(

)

Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, United Kingdom, EH4 2XR

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Abstract

The role of macroautophagy (hereafter autophagy) in cancer biology and response to clinical intervention is complex. It is clear that autophagy is dysregulated in a wide variety of tumor settings, both during tumor initiation and progression, and in response to therapy. However, the pleiotropic mechanistic roles of autophagy in controlling cell behavior make it difficult to predict in a given tumor setting what the role of autophagy, and, by extension, the therapeutic outcome of targeting autophagy, might be. In this review we summarize the evidence in the literature supporting pro- and anti-tumorigenic and-therapeutic roles of autophagy in cancer. This overview encompasses roles of autophagy in nutrient management, cell death, cell senescence, regulation of proteotoxic stress and cellular homeostasis, regulation of tumor-host interactions and participation in changes in metabolism. We also try to understand, where possible, the mechanistic bases of these roles for autophagy. We specifically expand on the emerging role of genetically-engineered mouse models of cancer in shedding light on these issues in vivo. We also consider how any or all of the above functions of autophagy proteins might be targetable by extant or future classes of pharmacologic agents. We conclude by briefly exploring non-canonical roles for subsets of the key autophagy proteins in cellular processes, and how these might impact upon cancer.

Keywords autophagy cancer inflammation metabolism apoptosis homeostasis

Corresponding Author(s): Simon WILKINSON

Issue Date: 13 May 2014

Cite this article:

Noor GAMMOH,Simon WILKINSON. Autophagy in cancer biology and therapy[J]. Front. Biol., 2014, 9(1): 35-50.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-014-1294-2
https://academic.hep.com.cn/fib/EN/Y2014/V9/I1/35

Fig.1 Molecular mechanism of autophagy. 1) Nucleation of the pre-autophagosome structure requires the recruitment of the upstream ATG complexes including the Vps34, ULK and ATG5 complexes. The molecular mechanisms underlying the membrane recruitment of these complexes and their subsequent dissociation upon maturation of the autophagosome are unknown. 2) Maturation of the pre-autophagosome requires the conjugation of cytosolic LC3-I to membrane bound LC3-II catalyzed by E1-, E2- and E3- like enzymes (ATG7, ATG3 and ATG5-ATG12, respectively). The maturing pre-autophagosome encapsulates cytosolic material (such as damaged mitochondria, unfolded proteins and organelles). Selective autophagy can be achieved through the ability of adaptor proteins (such as p62) to interact with LC3 and cellular substrates. 3) Autophagosome-lysosome fusion, resulting in autolysosome formation, is essential for autophagy flux. The molecular players facilitating this step are largely unknown. 4) Degradation of the autophagosome content is catalyzed by lysosomal proteases resulting in the recycling of nutrients and energy back to the cytoplasm. The conclusion of this step denotes a complete autophagic flux.

Tab.1 Summary of pro- and anti- cancer processes which autophagy promotes. Each of these may be a composite of multiple mechanistic roles of autophagy, determined by the work of several groups. Please see the text for details.

Fig.2 Potential manipulation of autophagy during anti-cancer therapy. Highlighted using red lines are potential molecules that can be targeted to inhibit autophagy meanwhile in green line are potential ways to activate autophagy. 1) Autophagy can be activated using anti-cancer agents (e.g. Etoposide & Cisplatin), mTOR inhibitors (e.g. Rapamycin & CCI-779), small peptides and leucine starvation. 2) Inhibiting ULK1 kinase activity is of interest to disrupt autophagy. However, ULK complex proteins have non-autophagic functions and autophagy can take place in their absence. 3) The class III PI3K, Vps34, is currently being targeted to inhibit autophagy using inhibitors such as 3-MA and wortmannin. Vps34 is also involved in endosomal trafficking and its inhibition can disrupt autophagy as well as multiple cellular functions. 4) Targeting core autophagy machinery may provide some specificity. Individual members of the ATG5 complex have autophagy-independent activities involving DNA damage response, apoptosis, immune response and mitochondrial function. Disrupting the complex formation (e.g. by inhibiting ATG5-ATG12 conjugation) may specifically abrogate autophagy. E1- and E2-like enzymes have non-autophagy functions; however targeting their enzymatic activities may lead to specific inhibition of autophagy. 5) Potential disruption of autophagosome-lysosome fusion may be specific to autophagy. The molecular players involved are not yet identified. 6) Pharmacological inhibition of lysosome function (e.g. using CQ or Bafilomycin A1) may affect carcinogenesis independently of autophagy. Furthermore, the disruption of autophagy at either early stages involving autophagosome formation or later events that abrogate autophagic degradation can lead to differential consequences during anti-cancer therapy as discussed in the text.

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