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Vol. 19, Issue 3, 797-806, March 2008

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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival

Christopher Fung^*, Rebecca Lock^*,, Sizhen Gao, Eduardo Salas^*, and Jayanta Debnath^*,

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

Submitted October 30, 2007; Revised December 1, 2007; Accepted December 12, 2007
Monitoring Editor: Donald Newmeyer

Autophagy has been proposed to promote cell death during lumen formation in three-dimensional 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. RNA interference-mediated depletion of autophagy regulators (ATGs) inhibits detachment-induced autophagy, enhances apoptosis, and reduces clonogenic recovery after 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 after 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 antiapoptotic lesions.

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

Abbreviations used: ATG, autophagy gene; AMPK, AMP-activated protein kinase; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; eIF2, eukaryotic initiation factor 2; GFP-LC3, green fluorescent protein fused to light chain 3; LC3, light chain 3; PE, phosphotidylethanolamine; 3D, three-dimensional.

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