Mcl-1 is an important therapeutic target for oral squamous cell carcinomas
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Santanu Maji1,2,*, Sabindra K Samal1,2,*, Laxmipriya Pattanaik1, Swagatika Panda3, Bridget A. Quinn4, Swadesh K. Das4,5,6, Devanand Sarkar4,5,6, Maurizio Pellecchia7, Paul B. Fisher4,5,6, Rupesh Dash1
1Institute of Life Sciences, Bhubaneswar, Odisha, India
2Manipal University, Karnataka, India
3Department of Oral Pathology & Microbiology, Institute of Dental Sciences, ‘Siksha O Anusandhan’ University, Bhubaneswar, Odisha, India
4Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
5VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
6VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
7Sanford-Burnham Medical Research Institute, La Jolla, California, USA
*These authors have contributed equally to this work
Rupesh Dash, e-mail: [email protected]
Keywords: Mcl-1, OSCC, mitophagy, sabutoclax, 4-NQO
Received: January 04, 2015 Accepted: April 30, 2015 Published: May 14, 2015
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.
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