title: Mcl-1 is an important therapeutic target for oral squamous cell carcinomas.
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-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.
authors.affiliation: Institute of Life Sciences, Bhubaneswar, Odisha, India.|Manipal University, Karnataka, India.
authors.forename: Santanu
authors.initials: S
authors.lastname: Maji
authors.affiliation: Institute of Life Sciences, Bhubaneswar, Odisha, India.|Manipal University, Karnataka, India.
authors.forename: Sabindra K
authors.initials: SK
authors.lastname: Samal
authors.affiliation: Institute of Life Sciences, Bhubaneswar, Odisha, India.
authors.forename: Laxmipriya
authors.initials: L
authors.lastname: Pattanaik
authors.affiliation: Department of Oral Pathology & Microbiology, Institute of Dental Sciences, 'Siksha O Anusandhan' University, Bhubaneswar, Odisha, India.
authors.forename: Swagatika
authors.initials: S
authors.lastname: Panda
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Institute of Life Sciences, Bhubaneswar, Odisha, India.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D000068579:Celecoxib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005260:Female; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics; D063306:Mitophagy / Q000187:drug effects; D009062:Mouth Neoplasms / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015363:Quinolones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011897:Random Allocation; D013449:Sulfonamides / Q000494:pharmacology*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: C550162:1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; C120195:4-nitroquinolone-1-oxide; C501332:ABT-737; C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; C090121:BNIP3 protein, human; D000071186:Beclin-1; D001713:Biphenyl Compounds; D052246:Cyclooxygenase 2 Inhibitors; C579095:MCL1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D015363:Quinolones; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051020:bcl-X Protein; D015112:4-Nitroquinoline-1-oxide; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D000068579:Celecoxib; D006072:Gossypol
keywords: 4-NQO; Mcl-1; OSCC; mitophagy; sabutoclax