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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival
Open accessAbstract
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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“Anoikis, a form of apoptosis caused by inappropriate cell/ECM interactions, has been reported in the formation of the lumen during the development of various secretory glands such as mammary and salivary glands.[20,21]”
From Autophagy, not apoptosis, plays a role in lumen formation of eccrine gland organoids (2022) · cites this paper as [21]
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Metadata
- 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
- Published
- 2008-03
- Volume
- 19
- Issue
- 3
- Pages
- 797-806
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- 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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