title: Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells.
abstract: Detachment of nonmalignant intestinal epithelial cells from the extracellular matrix (ECM) triggers their growth arrest and, ultimately, apoptosis. In contrast, colorectal cancer cells can grow without attachment to the ECM. This ability is critical for their malignant potential. We found previously that detachment-induced growth arrest of nonmalignant intestinal epithelial cells is driven by their detachment-triggered autophagy, and that RAS, a major oncogene, promotes growth of detached cells by blocking such autophagy. In an effort to identify the mechanisms of detachment-induced autophagy and growth arrest of nonmalignant cells we found here that detachment of these cells causes upregulation of ATG3 and that ATG3 upregulation contributes to autophagy and growth arrest of detached cells. We also observed that when ATG3 expression is artificially increased in the attached cells, ATG3 promotes neither autophagy nor growth arrest but triggers their apoptosis. ATG3 upregulation likely promotes autophagy of the detached but not that of the attached cells because detachment-dependent autophagy requires other detachment-induced events, such as the upregulation of ATG7. We further observed that those few adherent cells that do not die by apoptosis induced by ATG3 become resistant to apoptosis caused by cell detachment, a property that is critical for the ability of normal epithelial cells to become malignant. We conclude that cell-ECM adhesion can switch ATG3 functions: when upregulated in detached cells in the context of other autophagy-promoting events, ATG3 contributes to autophagy. However, when overexpressed in the adherent cells, in the circumstances not favoring autophagy, ATG3 triggers apoptosis.
authors.affiliation: a Departments of Pediatrics & Biochemistry and Molecular Biology ; Dalhousie University ; Halifax , NS Canada.
authors.forename: Byong Hoon
authors.initials: BH
authors.lastname: Yoo
authors.forename: Anna
authors.initials: A
authors.lastname: Zagryazhskaya
authors.forename: Yongling
authors.initials: Y
authors.lastname: Li
authors.forename: Ananda
authors.initials: A
authors.lastname: Koomson
authors.forename: Iman Aftab
authors.initials: IA
authors.lastname: Khan
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.forename: Kirill V
authors.initials: KV
authors.lastname: Rosen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007421:Intestine, Small / Q000473:pathology; D007422:Intestines / Q000166:cytology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010453:Peptide Synthases / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C561242:Atg7 protein, rat; D000071183:Autophagy-Related Proteins; C502070:MAP1LC3B protein, human; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D049452:Green Fluorescent Proteins; D044763:Ubiquitin-Conjugating Enzymes; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; C455621:ATG3 protein, human; C515644:Atg3 protein, rat; D010453:Peptide Synthases
keywords: ATG3; ATG7; anoikis; apoptosis; autophagy; extracellular matrix