Work

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

Year: 2015

Type: article

Abstract: // Santanu Maji 1, 2, * , Sabindra K Samal 1, 2, * , Laxmipriya Pattanaik 1 , Swagatika Panda 3 , Bridget A. Quinn 4 , Swadesh K. Das 4, 5, 6 , Devanand Sarkar 4, 5, 6 , Maurizio Pellecchia 7 , Paul B. Fisher 4, 5, 6 , Rupesh Dash 1 1 Institute of Life Sciences, Bhubaneswar, Odisha, India 2 Manipal University, Karnataka, India 3 Department of Oral Pathology & Microbiology, Institute of Dental Sciences, ‘Siksha O Anusandhan’ University, Bhubaneswar, Odisha, India 4 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA 5 VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA 6 VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA 7 Sanford-Burnham Medical Research Institute, La Jolla, California, USA * These authors have contributed equally to this work Correspondence to: 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 ABSTRACT 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-x L 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.3932