Mcl-1 is an important therapeutic target for oral squamous cell carcinomas

Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the B...

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Main Authors:	Maji, Santanu, Samal, Sabindra K, Pattanaik, Laxmipriya, Panda, Swagatika, Quinn, Bridget A., Das, Swadesh K., Sarkar, Devanand, Pellecchia, Maurizio, Fisher, Paul B., Dash, Rupesh
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599294/

id	pubmed-4599294
recordtype	oai_dc
spelling	pubmed-45992942015-10-26 Mcl-1 is an important therapeutic target for oral squamous cell carcinomas Maji, Santanu Samal, Sabindra K Pattanaik, Laxmipriya Panda, Swagatika Quinn, Bridget A. Das, Swadesh K. Sarkar, Devanand Pellecchia, Maurizio Fisher, Paul B. Dash, Rupesh Research Paper Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored. In this study, we found that knocking down Mcl-1 sensitized OSCC cells to ABT-737, which binds to Bcl-2/Bcl-xL but not Mcl-1. We report for the first time that a BH3 mimetic, Sabutoclax, which functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, induced cancer-specific cell death in an Mcl-1-dependent manner through both apoptosis and toxic mitophagy. In vivo studies demonstrated that Sabutoclax alone decreased tumor growth in a carcinogen-induced tongue OSCC mouse model. In a combination regimen, Sabutoclax and COX-2 inhibitor, Celecoxib, synergistically inhibited the growth of OSCC in vitro and also significantly reduced OSCC tumor growth in vivo. Overall, these results identify Mcl-1 as a therapeutic prospective target in OSCC. Impact Journals LLC 2015-05-14 /pmc/articles/PMC4599294/ /pubmed/26009874 Text en Copyright: © 2015 Maji et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Maji, Santanu Samal, Sabindra K Pattanaik, Laxmipriya Panda, Swagatika Quinn, Bridget A. Das, Swadesh K. Sarkar, Devanand Pellecchia, Maurizio Fisher, Paul B. Dash, Rupesh
spellingShingle	Maji, Santanu Samal, Sabindra K Pattanaik, Laxmipriya Panda, Swagatika Quinn, Bridget A. Das, Swadesh K. Sarkar, Devanand Pellecchia, Maurizio Fisher, Paul B. Dash, Rupesh Mcl-1 is an important therapeutic target for oral squamous cell carcinomas
author_facet	Maji, Santanu Samal, Sabindra K Pattanaik, Laxmipriya Panda, Swagatika Quinn, Bridget A. Das, Swadesh K. Sarkar, Devanand Pellecchia, Maurizio Fisher, Paul B. Dash, Rupesh
author_sort	Maji, Santanu
title	Mcl-1 is an important therapeutic target for oral squamous cell carcinomas
title_short	Mcl-1 is an important therapeutic target for oral squamous cell carcinomas
title_full	Mcl-1 is an important therapeutic target for oral squamous cell carcinomas
title_fullStr	Mcl-1 is an important therapeutic target for oral squamous cell carcinomas
title_full_unstemmed	Mcl-1 is an important therapeutic target for oral squamous cell carcinomas
title_sort	mcl-1 is an important therapeutic target for oral squamous cell carcinomas
description	Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored. In this study, we found that knocking down Mcl-1 sensitized OSCC cells to ABT-737, which binds to Bcl-2/Bcl-xL but not Mcl-1. We report for the first time that a BH3 mimetic, Sabutoclax, which functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, induced cancer-specific cell death in an Mcl-1-dependent manner through both apoptosis and toxic mitophagy. In vivo studies demonstrated that Sabutoclax alone decreased tumor growth in a carcinogen-induced tongue OSCC mouse model. In a combination regimen, Sabutoclax and COX-2 inhibitor, Celecoxib, synergistically inhibited the growth of OSCC in vitro and also significantly reduced OSCC tumor growth in vivo. Overall, these results identify Mcl-1 as a therapeutic prospective target in OSCC.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599294/
_version_	1613485701881397248

Mcl-1 is an important therapeutic target for oral squamous cell carcinomas

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