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MBC in Press, published online ahead of print December 19, 2007
Mol. Biol. Cell 10.1091/mbc.E07-10-1092

A more recent version of this article appeared on March 1, 2008
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Submitted on October 30, 2007
Revised on December 1, 2007
Accepted on December 12, 2007

Induction of Autophagy During Extracellular Matrix Detachment Promotes Cell Survival

Christopher Fung,* Rebecca Lock,*{dagger} Sizhen Gao,{ddagger} Eduardo Salas,* and Jayanta Debnath*{dagger}

*Department of Pathology, University of California San Francisco, San Francisco, CA 94143; {dagger}Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143; {ddagger}Department of Cell Biology, Harvard Medical School, Boston, MA, 02115

Monitoring Editor: Donald Newmeyer

Autophagy has been proposed to promote cell death during lumen formation in three-dimensional (3D) mammary epithelial acini because numerous autophagic vacuoles are observed in the dying central cells during morphogenesis. Because these central cells die due to extracellular matrix (ECM) deprivation (anoikis), we have directly interrogated how matrix detachment regulates autophagy. Detachment induces autophagy in both nontumorigenic epithelial lines and in primary epithelial cells. RNAi-mediated depletion of autophagy regulators (ATGs) inhibits detachment-induced autophagy, enhances apoptosis and reduces clonogenic recovery following anoikis. Remarkably, matrix-detached cells still exhibit autophagy when apoptosis is blocked by Bcl-2 overexpression, and ATG depletion reduces the clonogenic survival of Bcl-2-expressing cells following detachment. Finally, stable reduction of ATG5 or ATG7 in MCF-10A acini enhances luminal apoptosis during morphogenesis and fails to elicit long-term luminal filling, even when combined with apoptotic inhibition mediated by Bcl-2 overexpression. Thus, autophagy promotes epithelial cell survival during anoikis, including detached cells harboring anti-apoptotic lesions.

Address correspondence to: Jayanta Debnath (Jayanta.Debnath{at}ucsf.edu)






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