FoxM1 Suppression Sensitizes Laryngeal Carcinoma Hep-2 Cells To Cisplatin And The Related Mechanisms

Background:Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancer in China. The current therapeutic options for early stage laryngeal carcinoma include various types of laryngectomy. For advanced disease, combined therapies are often used. Furthermore, the survival rate has remained relatively low; one of the reason is likely due to the resistance to chemotherapy. While cisplatin can be clinically effective in the treatment of the advanced stage of laryngeal carcinoma, resistance does occur. Forkhead box protein M1 (FoxM1), a member of the forkhead transcription factor family, plays an important role in maintaining proliferation, embryonic development, differentiation, FoxM1 also regulates cellular viability by modulating apoptosis. Dysfunction of FoxM1 can drive malignant transformation, and FoxM1 is overexpressed in several malignancies. Some results suggest that FoxM1 plays a key role in tumor development, and may also play an important role in drug resistance. Thiostrepton, a natural antibiotic directly interacts with FoxM1 and can inhibit its expression. We have previously reported that FoxM1 is overexpressed in LSCC, Furthermore, targeting FoxM1 using thiostrepton can inhibit the expression of FoxMl in Hep-2 cells. However, the relationship between FoxMl overexpression and cisplatin resistance in Hep-2 cells is currently unclear.Objective:To explore whether down-regulation of FoxM1 modulates the cisplatin sensitivity of human laryngeal carcinoma Hep-2 cell and uncover the potential mechanisms.Methods:Small interfering RNA (siRNA) and FoxMl inhibitor thiostrepton were used to suppress FoxM1 expression of Hep-2 cells separately. The changes of FoxM1 mRNA and protein expression were confirmed by QRT-PCR and Western Blot. Cell viability and apoptosis of Hep-2 cells were detected by MTT assay and flow cytometry. Furthermore, QRT-PCR and Western Blot was used to investigate the changes of FoxMl of Hep-2 cells with FoxM1 suppression and cisplatin treatment. The change of apoptosis-ralated proteins were detected by Western Blot.Results:Both of siRNA and thiostrepton could suppress FoxMl expression(p<0.05); Both of si-FoxM1 and FoxM1 inhibitor could enhance survival rate and IC50. NC IC50=2.61±0.102, si-FoxM1 IC50=0.771± 0.058, P<0.05; control IC50=2.142±0.199, TSTIC50=0.773±0.063, P<0.05. and both of si-FoxM1 and FoxM1 inhibitor could enhance apoptosis rate of Hep-2 cell. siRNA:NC (4.1967±0.2727)%、si-FoxM1 (12.5533±0.1828)%, NC+ cisplatin (37.465±4.305)%. si-FoxM1+ cisplatin (82.3733±7.2142)%, P<0.05; TST:control(2.3433±0.1936)%、 TST (10.1267±0.4788)%, cisplatin (35.075±1.995)%, TST+ cisplatin (62.8433±1.8241)%, P<0.05. And both of them could inhibit Bcl-2 expression and up-regulate Bax expression.Conclusion:FoxMl plays an important role in cisplatin sensitivity of Hep-2 cells, and the mechanism is potentially relative to apoptosis-ralated protein.