Induction of Autophagy During Extracellular Matrix Detachment Promotes Cell Survival

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2007 Dec 21

PMID 18094039

Citations 309

Authors

Christopher Fung

Rebecca Lock

Sizhen Gao

Eduardo Salas

Jayanta Debnath

Affiliations

Soon will be listed here.

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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References

Reginato M, Mills K, Paulus J, Lynch D, Sgroi D, Debnath J . Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol. 2003; 5(8):733-40. DOI: 10.1038/ncb1026. View

Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson C . Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004; 6(12):1221-8. DOI: 10.1038/ncb1192. View

Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S . Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004; 304(5676):1500-2. DOI: 10.1126/science.1096645. View

Lee C, Baehrecke E . Steroid regulation of autophagic programmed cell death during development. Development. 2001; 128(8):1443-55. DOI: 10.1242/dev.128.8.1443. View

Meredith Jr J, Fazeli B, Schwartz M . The extracellular matrix as a cell survival factor. Mol Biol Cell. 1993; 4(9):953-61. PMC: 275725. DOI: 10.1091/mbc.4.9.953. View

Underwood J, Imbalzano K, Weaver V, Fischer A, Imbalzano A, Nickerson J . The ultrastructure of MCF-10A acini. J Cell Physiol. 2006; 208(1):141-8. DOI: 10.1002/jcp.20639. View

Talloczy Z, Jiang W, Virgin 4th H, Leib D, Scheuner D, Kaufman R . Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci U S A. 2002; 99(1):190-5. PMC: 117537. DOI: 10.1073/pnas.012485299. View

Lum J, Bauer D, Kong M, Harris M, Li C, Lindsten T . Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 2005; 120(2):237-48. DOI: 10.1016/j.cell.2004.11.046. View

Rytomaa M, Lehmann K, Downward J . Matrix detachment induces caspase-dependent cytochrome c release from mitochondria: inhibition by PKB/Akt but not Raf signalling. Oncogene. 2000; 19(39):4461-8. DOI: 10.1038/sj.onc.1203805. View

10.

Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan R . Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell. 2007; 128(5):931-46. DOI: 10.1016/j.cell.2006.12.044. View

11.

Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T . The role of autophagy during the early neonatal starvation period. Nature. 2004; 432(7020):1032-6. DOI: 10.1038/nature03029. View

12.

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A . Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003; 112(12):1809-20. PMC: 297002. DOI: 10.1172/JCI20039. View

13.

Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S . Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007; 21(13):1621-35. PMC: 1899472. DOI: 10.1101/gad.1565707. View

14.

Liang J, Shao S, Xu Z, Hennessy B, Ding Z, Larrea M . The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol. 2007; 9(2):218-24. DOI: 10.1038/ncb1537. View

15.

Meley D, Bauvy C, Houben-Weerts J, Dubbelhuis P, Helmond M, Codogno P . AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem. 2006; 281(46):34870-9. DOI: 10.1074/jbc.M605488200. View

16.

Debnath J, Mills K, Collins N, Reginato M, Muthuswamy S, Brugge J . The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell. 2002; 111(1):29-40. DOI: 10.1016/s0092-8674(02)01001-2. View

17.

Mathew R, Kongara S, Beaudoin B, Karp C, Bray K, Degenhardt K . Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007; 21(11):1367-81. PMC: 1877749. DOI: 10.1101/gad.1545107. View

18.

Debnath J, Muthuswamy S, Brugge J . Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003; 30(3):256-68. DOI: 10.1016/s1046-2023(03)00032-x. View

19.

Levine B, Klionsky D . Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004; 6(4):463-77. DOI: 10.1016/s1534-5807(04)00099-1. View

20.

Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E . Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci U S A. 2006; 103(13):4952-7. PMC: 1458776. DOI: 10.1073/pnas.0511288103. View