Thomas J Ow1,2, Carlos Thomas2, Cory D Fulcher1, Jianhong Chen3, Andrea López4, Denis E Reyna4, Michael B Prystowsky2, Richard V Smith1,2,5, Bradley A Schiff1, Gregory Rosenblatt2, Thomas J Belbin2,6, Thomas M Harris2, Geoffrey C Childs2, Nicole Kawachi2, Nicolas F Schlecht2,7,8,3, Evripidis Gavathiotis4. 1. Department of Otorhinolaryngology-Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. 2. Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. 3. Department of Cancer Prevention & Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, U.S.A. 4. Department of Biochemistry, Department of Medicine, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, U.S.A. 5. Department of Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. 6. Department of Oncology, Memorial University of Newfoundland, Newfoundland and Labrador, Canada. 7. Department of Epidemiology & Population Health, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. 8. Department of Medicine (Oncology), Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A.
Abstract
OBJECTIVES: To evaluate BCL-2 family signaling molecules in head and neck squamous cell carcinoma (HNSCC) and examine the ability of therapeutic agents with variable mechanisms of action to induce apoptosis in HNSCC cells. METHODS: messenger ribonculeic acid (mRNA) expression of BAK, BAX, B-cell lymphoma (Bcl-2), BCL2 Like 1 (BCL2L1), and MCL1 were measured in The Cancer Genome Atlas (TCGA) head and neck cancer dataset, as well as in a dataset from a cohort at Montefiore Medical Center (MMC). Protein expression was similarly evaluated in a panel of HNSCC cell lines (HN30, HN31, HN5, MDA686LN, UMSCC47). Cell viability and Annexin V assays were used to assess the efficacy and apoptotic potential of a variety of agents (ABT-263 [navitoclax], A-1210477, and bortezomib. RESULTS: Expression of BAK, BAX, BCL2L1, and MCL1 were each significantly higher than expression of BCL2 in the TCGA and MMC datasets. Protein expression demonstrated the same pattern of expression when examined in HNSCC cell lines. Treatment with combined ABT-263 (navitoclax)/A-1210477 or with bortezomib demonstrated apoptosis responses that approached or exceeded treatment with staurospaurine control. CONCLUSION: HNSCC cells rely on inhibition of apoptosis via BCL-xL and MCL-1 overexpression, and induction of apoptosis remains a potential therapeutic option as long as strategies overcome redundant anti-apoptotic signals. LEVEL OF EVIDENCE: NA Laryngoscope, 130:2643-2649, 2020.
OBJECTIVES: To evaluate BCL-2 family signaling molecules in head and neck squamous cell carcinoma (HNSCC) and examine the ability of therapeutic agents with variable mechanisms of action to induce apoptosis in HNSCC cells. METHODS: messenger ribonculeic acid (mRNA) expression of BAK, BAX, B-cell lymphoma (Bcl-2), BCL2 Like 1 (BCL2L1), and MCL1 were measured in The Cancer Genome Atlas (TCGA) head and neck cancer dataset, as well as in a dataset from a cohort at Montefiore Medical Center (MMC). Protein expression was similarly evaluated in a panel of HNSCC cell lines (HN30, HN31, HN5, MDA686LN, UMSCC47). Cell viability and Annexin V assays were used to assess the efficacy and apoptotic potential of a variety of agents (ABT-263 [navitoclax], A-1210477, and bortezomib. RESULTS: Expression of BAK, BAX, BCL2L1, and MCL1 were each significantly higher than expression of BCL2 in the TCGA and MMC datasets. Protein expression demonstrated the same pattern of expression when examined in HNSCC cell lines. Treatment with combined ABT-263 (navitoclax)/A-1210477 or with bortezomib demonstrated apoptosis responses that approached or exceeded treatment with staurospaurine control. CONCLUSION: HNSCC cells rely on inhibition of apoptosis via BCL-xL and MCL-1 overexpression, and induction of apoptosis remains a potential therapeutic option as long as strategies overcome redundant anti-apoptotic signals. LEVEL OF EVIDENCE: NA Laryngoscope, 130:2643-2649, 2020.
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