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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro.

ABSTRACT: The molecular events regulating the elimination of cells to create a hollow lumen during tissue development are poorly understood. By using an in vitro morphogenesis model in which MCF-10A human mammary epithelial cells form hollow acini-like structures, we have observed both caspase-mediated apoptosis and autophagy associated with cells that are lost during lumen formation. Here, we show that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates induction of autophagic processes associated with lumen formation. TRAIL is up-regulated during morphogenesis of MCF-10A mammary epithelial cells in 3D basement-membrane cultures and inhibition of TRAIL signaling during morphogenesis blocks the formation of autophagic vacuoles. In addition, treatment with exogenous TRAIL induces extensive autophagy in monolayer and 3D cultures. When combined with inhibition of caspase 3 activity (by Bcl-X(L) overexpression), inhibition of TRAIL-induced autophagy results in luminal filling. Thus, TRAIL regulates an autophagic program during acinar morphogenesis, which together with caspase-mediated apoptotic events, results in lumen formation during MCF-10A morphogenesis.

SUBMITTER: Mills KR

PROVIDER: S-EPMC373480 | biostudies-literature | 2004 Mar

REPOSITORIES: biostudies-literature

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro.

Mills Kenna R KR Reginato Mauricio M Debnath Jayanta J Queenan Bridget B Brugge Joan S JS

Proceedings of the National Academy of Sciences of the United States of America 20040301 10

The molecular events regulating the elimination of cells to create a hollow lumen during tissue development are poorly understood. By using an in vitro morphogenesis model in which MCF-10A human mammary epithelial cells form hollow acini-like structures, we have observed both caspase-mediated apoptosis and autophagy associated with cells that are lost during lumen formation. Here, we show that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates induction of autophagic pr ...[more]

PMID: 14993595

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Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other âdeath receptorâ ligands may explain not only the inability of TRAIL and TRAIL âdeath receptorâ agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell â mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). We showed that acquired TRAIL resistance was associated with complex disruption of both extrinsic and intrinsic apoptotic pathways manifested by acquired multi-drug resistant phenotype of TR1, TR2, and TR3 clones. To identify changes associated with TRAIL resistance of Jurkat cells we performed genome-wide gene expression analysis of TRAIL-resistant clones (TR) and compared to WT Jurkat cells. We identified significantly increased expression (1.33-fold change with adjusted p < 0.05) of 73 genes in TR1 clone, 53 genes in TR2 clone and 8 genes in TR3 clone, and significant decrease in expression (0.75-fold change with adjusted p < 0.05) of 174 genes in TR1 clone, 36 genes in TR2 clone and 28 genes in TR3 clone. There was an overlap of only 2 significantly overexpressed (midkine / MDK and zinc finger and BTB domain containing 16 gene / ZBTB16 / PLZF) and 4 downregulated genes (YAP1, IGJ, EIF1AY, RPS4Y1) in all three TR clones. Total cellular RNA was isolated from biologic duplicates of untreated Jurkat cells (WT) and TRAIL resistant Jurkat cell line subclones (TR1, TR2, TR3) established by selective pressure of TRAIL 1000 ng/mL on Jurkat cells over the period of 12 weeks.

Dataset Information

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro.

Publications

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro.

Similar Datasets

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