Cited by 558Autophagy in Disease and TherapyCell death mechanisms and regulationUbiquitin and proteasome pathways

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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival

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Fung, Christopher, Lock, Rebecca, Gao, Sizhen, Salas, Eduardo, Debnath, Jayanta·2008·Molecular Biology of the Cell

DOI 10.1091/mbc.e07-10-1092PMC PMC2262959

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Abstract

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.

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Authors: Fung, C., Lock, R., Gao, S., Salas, E., & Debnath, J.
Affiliations: University of California, San Francisco (US)
Harvard University (US)
*Department of Pathology and
ORCID: Debnath, Jayanta
Venue: Molecular Biology of the Cell
Publisher: American Society for Cell Biology (ASCB)
Published: 2008-03
Volume: 19
Issue: 3
Pages: 797-806
ISSN: 1059-1524 (ISSN-L)
1939-4586
DOI: 10.1091/mbc.e07-10-1092
PMC: PMC2262959
OpenAlex: W2039403501
Cited by: 558
References: 52
Citations by year: 2026: 10 · 2025: 20 · 2024: 15 · 2023: 26 · 2022: 33 · 2021: 45 · 2020: 41 · 2019: 35 · 2018: 36 · 2017: 23 · 2016: 40 · 2015: 37 · 2014: 44 · 2013: 43 · 2012: 28
FWCI: 9.86
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Biology of the Cell (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
American Association for Cancer Research
National Institutes of Health
Genentech
University of California, San Francisco
National Cancer Institute (K08CA098419)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: autophagy, anoikis, extracellular matrix detachment, lumen formation, epithelial morphogenesis, apoptosis, Bcl-2, ATG5, ATG7, clonogenic survival, autophagy-related genes, mammary tumor cells
MeSH terms: Autophagy-Related Protein 5, Autophagy-Related Protein 7, Animals, Autophagy, Cell Adhesion, Cell Line, Cell Survival, Dogs, Epidermal Growth Factor, Epithelial Cells, Extracellular Matrix, Fibroblasts, Humans, Microtubule-Associated Proteins, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Ubiquitin-Activating Enzymes, Mice, ErbB Receptors

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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival

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