Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway

• Published in: Experimental cell research 2018-01, Vol.362 (2), p.362-369
• Main Authors: Jin, Yingying, Xu, Kun, Chen, Qingjuan, Wang, Baofeng, Pan, Jiyuan, Huang, Shan, Wei, Yang, Ma, Hongbing
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; CARCINOMAS; CELL PROLIFERATION; EMT; Esophageal cancer; ESOPHAGUS; MAMMARY GLANDS; PI3K/AKT; PTEN; Radioresistance; RADIOSENSITIVITY; RADIOTHERAPY; Simvastatin
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2017.11.037

Acquired radioresistance compromises the efficacy of radiotherapy for carcinomas including esophageal cancer (EC), thus resulting in recurrence and poor survival. Recent research corroborated radiosensitive function of simvastatin in stem-like breast cancer cells. However, its role in EC radioresistance remains poorly elucidated. Here, we developed a radioresistant EC cell line Ec9706-R with higher resistance to irradiation relative to control Ec9706 cells. Intriguingly, Ec9706-R cells exhibited epithelial-mesenchymal transition (EMT) characteristics with high invasion and migration ability. Simvastatin sensitized radioresistance of Ec9706-R cells and suppressed cell proliferation, but aggravated radiation-induced apoptosis and caspase-3 activity. Furthermore, simvastatin reversed EMT and inhibited cell invasion and migration of Ec9706-R cells. Mechanism assay confirmed the activation of PI3K/AKT pathway after radiation, which was inhibited by simvastatin. After restoring this pathway by its activator, IGF-1, simvastatin-mediated radiosensitivity and EMT reversion were abrogated. Further assay substantiated the PTEN suppression after irradiation, which was elevated following simvastatin pre-treatment. Moreover, PTEN cessation attenuated the inhibitory effect of simvastatin on PI3K/AKT activation, and subsequently antagonized simvastatin-induced radiosensitivity and EMT reversion. Additionally, simvastatin aggravated radiation-mediated Ec9706-R tumor growth inhibition. Together, simvastatin inhibits the development of Ec9706-R cells by increasing radiosensitivity and reversing EMT via PTEN-PI3K/AKT pathway, implying a promising strategy against EC radioresistance. •Radioresistant Ec9706-R cells acquire EMT characteristics.•Simvastatin restores the sensitivity of Ec9706-R to irradiation.•Simvastatin suppresses irradiation-induced EMT.•PTEN-PI3K/AKT pathway involves in simvastatin-induced radiosensitivity, EMT reversion.•Simvastatin aggravates radiation-inhibited radioresistant EC xenograft tumor growth.