cFLIP critically modulates apoptotic resistance in epithelial-tomesenchymal 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; R. Daniel Beauchamp

doi:10.18632/oncotarget.19557

cFLIP critically modulates apoptotic resistance in epithelial-tomesenchymal 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, R. Daniel Beauchamp

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Epithelial cancers (carcinomas) comprise the top four causes of cancer-related deaths in the United States. While overall survival has been steadily improving, therapyresistant 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, cFLIP_S. Loss of cFLIP_S is sufficient to overcome resistance to TRAIL and exogenous overexpression of cFLIP_S restores resistance to TRAIL-induced apoptosis despite EMT reversal with ML327. In summary, we have utilized an isoxazolebased small molecule that partially reverses EMT in carcinoma cells to demonstrate that cFLIP_S critically regulates the apoptosis resistance phenotype associated with EMT.

Original language	English
Pages (from-to)	101072-101086
Number of pages	15
Journal	Oncotarget
Volume	8
Issue number	60
DOIs	https://doi.org/10.18632/oncotarget.19557
State	Published - 2017

Bibliographical note

Funding Information:
Flow cytometry experiments were performed in the VMC Flow Cytometry Shared Resource. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). RNA sequencing was performed in the Vanderbilt Technologies for Advanced Genomics (VANTAGE) Core. VANTAGE is supported in part by CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956).

Funding Information:
This work was supported by the NIH T32CA106183-10 Training Grant (Padmanabhan, Rellinger), the GI SPORE P50CA095103 (Beauchamp), and the John Clinton Foshee Endowment to the Vanderbilt University Medical Center Department of Surgery (Beauchamp).

Publisher Copyright:
© Padmanabhan et al.

Keywords

Apoptosis
CFLIP
EMT
Isoxazole
TRAIL

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.18632/oncotarget.19557

Cite this

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title = "cFLIP critically modulates apoptotic resistance in epithelial-tomesenchymal transition",

abstract = "Epithelial cancers (carcinomas) comprise the top four causes of cancer-related deaths in the United States. While overall survival has been steadily improving, therapyresistant 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 isoxazolebased 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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author = "Chandrasekhar Padmanabhan and Rellinger, {Eric J.} and Jing Zhu and Hanbing An and Woodbury, {Luke G.} and Chung, {Dai H.} and Waterson, {Alex G.} and Lindsley, {Craig W.} and Means, {Anna L.} and Beauchamp, {R. Daniel}",

note = "Funding Information: Flow cytometry experiments were performed in the VMC Flow Cytometry Shared Resource. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). RNA sequencing was performed in the Vanderbilt Technologies for Advanced Genomics (VANTAGE) Core. VANTAGE is supported in part by CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956). Funding Information: This work was supported by the NIH T32CA106183-10 Training Grant (Padmanabhan, Rellinger), the GI SPORE P50CA095103 (Beauchamp), and the John Clinton Foshee Endowment to the Vanderbilt University Medical Center Department of Surgery (Beauchamp). Publisher Copyright: {\textcopyright} Padmanabhan et al.",

year = "2017",

doi = "10.18632/oncotarget.19557",

language = "English",

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AU - Padmanabhan, Chandrasekhar

AU - Rellinger, Eric J.

AU - Zhu, Jing

AU - An, Hanbing

AU - Woodbury, Luke G.

AU - Chung, Dai H.

AU - Waterson, Alex G.

AU - Lindsley, Craig W.

AU - Means, Anna L.

AU - Beauchamp, R. Daniel

N1 - Funding Information: Flow cytometry experiments were performed in the VMC Flow Cytometry Shared Resource. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). RNA sequencing was performed in the Vanderbilt Technologies for Advanced Genomics (VANTAGE) Core. VANTAGE is supported in part by CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956). Funding Information: This work was supported by the NIH T32CA106183-10 Training Grant (Padmanabhan, Rellinger), the GI SPORE P50CA095103 (Beauchamp), and the John Clinton Foshee Endowment to the Vanderbilt University Medical Center Department of Surgery (Beauchamp). Publisher Copyright: © Padmanabhan et al.

PY - 2017

Y1 - 2017

N2 - Epithelial cancers (carcinomas) comprise the top four causes of cancer-related deaths in the United States. While overall survival has been steadily improving, therapyresistant 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 isoxazolebased small molecule that partially reverses EMT in carcinoma cells to demonstrate that cFLIPS critically regulates the apoptosis resistance phenotype associated with EMT.

AB - Epithelial cancers (carcinomas) comprise the top four causes of cancer-related deaths in the United States. While overall survival has been steadily improving, therapyresistant 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 isoxazolebased small molecule that partially reverses EMT in carcinoma cells to demonstrate that cFLIPS critically regulates the apoptosis resistance phenotype associated with EMT.

KW - Apoptosis

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KW - EMT

KW - Isoxazole

KW - TRAIL

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ER -

cFLIP critically modulates apoptotic resistance in epithelial-tomesenchymal transition

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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