Role and regulation of proapoptotic Bax in oral squamous cell carcinoma and drug resistance

• Published in: Head & neck 2019-01, Vol.41 (1), p.185-197
• Main Authors: Alam, Manzar, Kashyap, Tanushree, Mishra, Prajna, Panda, Aditya K., Nagini, Siddavaram, Mishra, Rajakishore
• Format: Article
• Language: English
• Subjects: Adult; Aged; Akt; AKT protein; Antineoplastic Agents - pharmacology; Apoptosis; Bax; BAX gene; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Bcl‐2; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; Cell death; Cell Line, Tumor; chemoradiation resistance; Chemoradiotherapy; Cisplatin; Cisplatin - pharmacology; Deoxyribonucleic acid; Disease Progression; DNA; DNA methylation; Drug resistance; Drug Resistance, Neoplasm; Female; GSK3α; GSK3β; Head and neck; Humans; Limonins - pharmacology; Male; Middle Aged; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Mouth Neoplasms - therapy; mRNA; Oncogene Protein v-akt - metabolism; Oral cancer; Oral squamous cell carcinoma; OSCC; p53; p53 Protein; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; RNA, Messenger - metabolism; Squamous cell carcinoma; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1043-3074; 1097-0347; 1097-0347
• DOI: 10.1002/hed.25471

Background Bax, a proapoptotic protein but its regulation during oral cancer progression and resistance remains elusive. Methods A total of 127 samples including adjacent normal, primary tumor, and resistance to chemoradiation therapy (RCRT) samples from oral squamous cell carcinoma (OSCC) patients were used. The status of Bax was analyzed at DNA/mRNA/protein levels and the results were correlated with p53 and Akt expression in tissue samples/cisplatin‐resistant oral tongue SCC (SCC9/SCC4‐CisR) cell line. Results Frequent progressive decrease of Bax expression with infrequent promoter methylation, polymorphisms G(‐248)A, and mutations was observed in OSCC progression/resistance. Furthermore, by targeting Akt pathway, induction of Bax‐dependent cell death was observed and this was further enhanced with nimbolide treatment in SCC9/SCC4‐CisR cells. Conclusion Hence, the Bax gene alteration and its deregulation through p53/Akt pathway are important for OSCC progression and drug resistance. Akt Inhibitor VIII and nimbolide synergistically induce Bax, and it is therefore beneficial for chemosensitizing cisplatin‐resistant human OSCC.