cFLIP critically modulates apoptotic resistance in epithelial-to-mesenchymal transition
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Chandrasekhar Padmanabhan1,2, Eric J. Rellinger1,2, Jing Zhu1,2, Hanbing An1,2, Luke G. Woodbury8, Dai H. Chung1,3,4, Alex G. Waterson5, Craig W. Lindsley6,7, Anna L. Means1,2 and R. Daniel Beauchamp1,2,4,8,9
1Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville TN, 37232, USA
2Department of Surgery, Vanderbilt University Medical Center, Nashville TN, 37232, USA
3Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville TN, 37232, USA
4Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville TN 37232, USA
5Department of Pharmacology, Vanderbilt University School of Medicine, Nashville TN, 37232, USA
6Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville TN, 37232, USA
7Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville TN, 37232, USA
8Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville TN, 37232, USA
9The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
R. Daniel Beauchamp, email: firstname.lastname@example.org
Keywords: EMT, apoptosis, cFLIP, TRAIL, isoxazole
Received: April 27, 2017 Accepted: June 26, 2017 Published: July 25, 2017
Epithelial cancers (carcinomas) comprise the top four causes of cancer-related deaths in the United States. While overall survival has been steadily improving, therapy-resistant disease continues to present a major therapeutic challenge. Carcinomas often exploit the normal developmental program, epithelial-to-mesenchymal transition (EMT), to gain a mesenchymal phenotype associated with increased invasiveness and resistance to apoptosis. We have previously shown that an isoxazole-based small molecule, ML327, partially reverses TGF-β-induced EMT in an immortalized mouse mammary epithelial cell line. Herein, we demonstrate that ML327 reverses much of the EMT gene expression program in cultured carcinoma cell lines. The reversal of EMT sensitizes these cancer cells to the apoptosis-inducing ligand TRAIL. This sensitization is independent of E-cadherin expression and rather relies on the downregulation of a major anti-apoptotic protein, cFLIPS. Loss of cFLIPS is sufficient to overcome resistance to TRAIL and exogenous overexpression of cFLIPS restores resistance to TRAIL-induced apoptosis despite EMT reversal with ML327. In summary, we have utilized an isoxazole-based small molecule that partially reverses EMT in carcinoma cells to demonstrate that cFLIPS critically regulates the apoptosis resistance phenotype associated with EMT.
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