Oncotarget

Research Papers:

cFLIP critically modulates apoptotic resistance in epithelial-to-mesenchymal transition

Chandrasekhar Padmanabhan, Eric J. Rellinger, Jing Zhu, Hanbing An, Luke G. Woodbury, Dai H. Chung, Alex G. Waterson, Craig W. Lindsley, Anna L. Means and R. Daniel Beauchamp _

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Oncotarget. 2017; 8:101072-101086. https://doi.org/10.18632/oncotarget.19557

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Abstract

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

Correspondence to:

R. Daniel Beauchamp, email: daniel.beauchamp@vanderbilt.edu

Keywords: EMT, apoptosis, cFLIP, TRAIL, isoxazole

Received: April 27, 2017     Accepted: June 26, 2017     Published: July 25, 2017

ABSTRACT

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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