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The role of autophagy in cancer development and response to therapy

Key Points

  • Autophagy is a process that describes the degradation and recycling of proteins and intracellular components in response to starvation or stress.

  • At the early stage of tumour development, autophagy functions as a tumour suppressor. Expression of beclin 1 (BECN1), a mammalian orthologue of the yeast autophagy-related gene Atg6, reduces tumorigenic capacity through induction of autophagy. Mice that are Becn1+/− display a remarkable increase in the incidence of lung cancer, hepatocellular carcinoma and lymphoma.

  • At advanced stages of tumour development, autophagy promotes tumour progression. The tumour cells that are located in the central area of the tumour mass undergo autophagy to survive low-oxygen and low-nutrient conditions.

  • Autophagy protects some cancer cells against anticancer treatments by blocking the apoptotic pathway ('protective autophagy'). By contrast, other cancer cells undergo autophagic cell death after cancer therapies.

  • Autophagy is induced mainly through the phosphatidylinositol 3-phosphate kinase (PI3K)–AKT–mTOR (mammalian target of rapamycin) signalling pathway.

  • Manipulation of autophagy has the potential to improve anticancer therapeutics. When tumour cells induce protective autophagy, inhibition of autophagy could sensitize tumour cells to the treatment by activating apoptosis. On the other hand, induction of autophagic cell death can also have a therapeutic value.

Abstract

Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy? And how can the autophagic process be manipulated to improve anticancer therapeutics?

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Figure 1: The cellular process of autophagy.
Figure 2: The molecular regulation of autophagy.
Figure 3: Potential strategies for treating cancer by manipulating the autophagic process.

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Acknowledgements

We thank Akitsugu Yamamoto (Nagahama Institute of Bio-Science and Technology, Nagahama, Japan) and Noboru Mizushima (Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) for their critical review, and Karen F. Phillips, ELS, for editing the manuscript. This work was supported in part by National Cancer Institute grants (S.K.), in part by a start-up fund (S.K.), Institutional Research grant (Y.K.), and a Cancer Center Support grant/Shared Resources from The University of Texas M. D. Anderson Cancer Center, and in part by a generous donation from the Anthony D. Bullock III Foundation (Y.K., R.S. and S.K.). We apologize to colleagues whose works on cancer-related autophagy have not been cited owing to space limitation.

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Correspondence to Seiji Kondo.

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DATABASES

Entrez Gene

AKT

ATG7

BECN1

BCL2

BNIP3

DAPK

DRP1

HSPIN1

mTOR

PTEN

National Cancer Institute

breast cancer

colon cancer

lung cancer

malignant glioma

Glossary

AUTOPHAGY

Lysosome-mediated degradation of proteins and cellular organelles. Autophagic cell death is referred to as type II programmed cell death.

AUTOPHAGOSOME

A membrane structure, formed inside cells during the process of autophagy, which sequesters cellular proteins and cytoplasmic organelles.

AUTOLYSOSOME

A membrane structure made by the fusion of an autophagosome and a lysosome.

APOPTOSIS

Referred to as type I programmed cell death. Characterized by a particular pattern of morphological changes, such as chromatin condensation or fragmentation.

TRANS-GOLGI NETWORK

The last three cisternae of the Golgi apparatus, which is made up of seven cisternae altogether. This is the exit compartment for newly made proteins that are on the way to their destinations.

PROGRAMMED CELL DEATH

An active cellular process that results in cell death. It takes place during normal development and in response to physiological damage such as that caused by cancer treatments.

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Kondo, Y., Kanzawa, T., Sawaya, R. et al. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5, 726–734 (2005). https://doi.org/10.1038/nrc1692

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