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.
Keywords:
4-NQO; Mcl-1; OSCC; mitophagy; sabutoclax.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Nitroquinoline-1-oxide / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / genetics
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Autophagy-Related Protein 5
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Autophagy-Related Protein 7
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Beclin-1
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Biphenyl Compounds / pharmacology*
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Carcinoma, Squamous Cell / drug therapy*
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Celecoxib / pharmacology*
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Cell Line, Tumor
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Cyclooxygenase 2 Inhibitors / pharmacology
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Female
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Gossypol / analogs & derivatives*
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Gossypol / pharmacology
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Humans
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Membrane Proteins / genetics
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Microtubule-Associated Proteins / genetics
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Mitophagy / drug effects
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Mouth Neoplasms / drug therapy*
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / genetics*
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Nitrophenols / pharmacology*
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Piperazines / pharmacology
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Proto-Oncogene Proteins / genetics
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Quinolones / pharmacology
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RNA Interference
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RNA, Small Interfering
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Random Allocation
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Sulfonamides / pharmacology*
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Ubiquitin-Activating Enzymes / genetics
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Xenograft Model Antitumor Assays
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bcl-X Protein / antagonists & inhibitors
Substances
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1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide
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4-nitroquinolone-1-oxide
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ABT-737
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ATG5 protein, human
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Apoptosis Regulatory Proteins
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Autophagy-Related Protein 5
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BCL2L1 protein, human
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BECN1 protein, human
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BNIP3 protein, human
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Beclin-1
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Biphenyl Compounds
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Cyclooxygenase 2 Inhibitors
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MCL1 protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins
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Quinolones
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RNA, Small Interfering
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Sulfonamides
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bcl-X Protein
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4-Nitroquinoline-1-oxide
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ATG7 protein, human
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Autophagy-Related Protein 7
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Ubiquitin-Activating Enzymes
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Celecoxib
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Gossypol