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Autophagy. 2014 Jan;10(1):173-5. doi: 10.4161/auto.26924. Epub 2013 Nov 15.

Autophagic degradation of GZMB/granzyme B: a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis.

Author information

1
Laboratory of Experimental Hemato-Oncology; Department of Oncology; Public Research Center for Health; Luxembourg City, Luxembourg.
2
INSERM U753; Institut de Cancérologie Gustave Roussy; Villejuif, France.

Abstract

The crucial issue for defining successful natural killer (NK)-based anticancer therapy is the ability of tumor cells to activate resistance mechanisms leading to escape from NK-mediated killing. It is now well established that such mechanisms are likely evolved under hypoxia in the tumor microenvironment. Here, we show that hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. This study provides a cutting-edge advance in our understanding of how hypoxia-induced autophagy impairs NK-mediated lysis and might pave the way for formulating more effective NK-based antitumor therapy by combining autophagy inhibitors.

KEYWORDS:

autophagy; breast cancer; granzyme B; hypoxia; natural killer

PMID:
24248158
PMCID:
PMC4389872
DOI:
10.4161/auto.26924
[Indexed for MEDLINE]
Free PMC Article
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