Autophagy is a critical catabolic process that promotes cellular homeostasis and allows cells to survive periods of starvation and other physiological stresses. The cellular matter degraded by autophagy is diverse and the identification of novel cargoes is an on-going effort. Included amongst known targets of autophagy are large cytoplasmic structures including protein aggregates, pathogens and an array of organelles including mitochondria, ER, ribosomes, peroxisomes and lipid droplets. Degrading such cargoes through selective autophagy promotes the function of the remaining mass of organelles but also contributes to the production of metabolites, and amino acids in particular, that are recycled at the lysosome to promote continued metabolism and growth.

The role of autophagy in cancer is clearly multifaceted with a growing body of work illustrating tumor suppressive functions in early stage disease and conversely a role in promoting tumor progression to metastasis. There also appear to be differences in the role of autophagy in cancer depending on tissue type and driving oncogene. Overall, autophagy could be contributing to tumorigenesis through modulating turnover of mitochondria and promoting mitochondrial metabolism (as reported in recent mouse models), eliminating unfolded proteins and reducing ER stress, promoting amino acid recycling for growth and metabolism, through effects on recruitment of tumor associated immune cells and anti-tumor immunosurveillance, possibly through secretion of cytokines and MMPs in addition to other functions in the tumor microenvironment. These many diverse activities of autophagy in cancer prompt us to investigate the relative contribution of specific forms of selective autophagy to tumorigenesis and also raises the question of whether modulating a specific form of selective autophagy might lead to more effective therapeutic approaches.

Our work has explored the effect of specifically targeting mitophagy in tumors through deletion of BNIP3, an outer mitochondrial membrane protein that interacts directly with LC3 to promote mitochondrial turnover at the autophagolysosome. We have examined effects of BNip3 loss on stress responses and tumorigenesis in the liver, pancreas and mammary gland and the emerging phenotypes diverge significantly from analysis of inhibiting general autophagy in these same tissues. Overall, we find that loss of BNip3 limits tumor initiation but promotes tumor progression. In essence, the effect of inhibiting BNip3-dependent mitophagy has the opposite effect on tumorigenesis to that observed when general autophagy is inhibited. Several explanations for these findings include the contribution of other aspects of general autophagy to tumorigenesis (such as amino acid recycling or the role played in the secretory phenotype), or alternatively, that mitophagy is not completely abrogated by loss of BNip3 and that other mitochondrial adaptor molecules can compensate, or finally that BNIP3 plays additional roles in the cell beyond its role in mitophagy that could influence the tumor phenotype. Our findings will be discussed in the wider context of other work in the field with the goal of identifying new research priorities to better understand the role of autophagy in cancer and how to manipulate it for therapeutic gain.

Citation Format: Kay F. Macleod. Contrasting consequences of autophagy deficiency and mitophagy deficiency in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY01-01. doi:10.1158/1538-7445.AM2015-SY01-01

©2015 American Association for Cancer Research.
2015