Research ArticleCancer

Chaperone-Mediated Autophagy Is Required for Tumor Growth

Science Translational Medicine  16 Nov 2011:
Vol. 3, Issue 109, pp. 109ra117
DOI: 10.1126/scitranslmed.3003182

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A LAMP Shines Light on Cancer Cell Death

The process of autophagy, which literally means self-eating, contributes to cellular homeostasis by ensuring that damaged or unwanted cellular components are degraded in organelles called lysosomes. The two best-characterized pathways of autophagy are macroautophagy and chaperone-mediated autophagy. Alterations in macroautophagy have been reported in cancer cells, but it is unclear whether chaperone-mediated autophagy is also altered in cancer cells. In a new study, Kon and colleagues explore the contribution of chaperone-mediated autophagy to tumor growth and metastasis in vitro and in a mouse xenograft model of human primary lung tumors.

Using biochemical and image-based techniques, the investigators found that chaperone-mediated autophagy is up-regulated in many cancer cell lines. Indeed, there were increases in the principal components of the chaperone-mediated autophagy pathway—including the key lysosomal receptor LAMP-2A (lysosome-associated membrane protein type 2A)—in more than 40 different types of human tumors when compared with normal tissue surrounding the tumors. To determine the importance of chaperone-mediated autophagy to the survival of cancer cells, the authors used short hairpin RNAs (shRNAs) to down-regulate LAMP-2A expression and hence the activity of this pathway. They discovered that tumor survival depended on the activity of this pathway and that blockade of chaperone-mediated autophagy in cancer cells delayed tumor growth and reduced metastasis. Next, the authors studied mice carrying xenografts of human primary lung tumors and showed that inhibition of chaperone-mediated autophagy by direct injection of shRNAs against LAMP-2A resulted in tumor shrinkage. Analysis of the metabolic status of cancer cells after inhibition of chaperone-mediated autophagy revealed that this pathway is essential for maintaining the high rate of cellular glycolysis that is characteristic of tumor cells.

These new findings establish that tumor cells require chaperone-mediated autophagy to maintain their cellular energetic balance through modulation of glycolysis and that cancer cells cannot survive without this pathway. Selective inhibition of chaperone-mediated autophagy may be a new strategy for preventing tumorigenesis and for boosting tumor regression.