Radiation-Induced Increase in Cell Migration and Metastatic Potential of Cervical Cancer Cells Operates Via the K-Ras Pathway

Radiotherapy is a well established treatment for cervical cancer, the second most common cancer in women worldwide. However, metastasis often circumvents the efficacy of radiotherapy. This study was conducted to elucidate the molecular mechanism of radioresistance-associated metastatic potential of cervical cancer cells. We established three radioresistant cervical cancer cell lines by exposure of cells to a sublethal dose of radiation and screened for lines that exhibited an increased migration phenotype for at least 6 months before undertaking mechanistic studies. Radiation-associated metastatic potential was evaluated using a wound-healing assay, time-lapse recording, and cell locomotion into the lungs of BALB/c nude mice. The radioresistant C33A and CaSki cell lines, but not the radioresistant HeLa cell line, exhibited significantly increased cell migration and wound healing than did wild-type cells. Furthermore, K-Ras played a prometastatic role via the activation of c-Raf/p38, whereas interference of those mediators via either RNA interference-mediated knockdown or the use of chemical inhibitors substantially reversed the radioresistance-associated increase in cell migration. Clinical examination further showed the relative upregulation of the K-Ras/c-Raf/p38 pathway in locally recurring tumors and distant metastases compared with in the primary cervical tumor. These findings demonstrate that a sublethal dose of radiation can enhance the metastatic potential of human cervical cancer cells via K-Ras/c-Raf/p38 signaling, highlighting the potential development of specific inhibitors for reducing metastatic potential during radiotherapy. (Am J Patbol 2012, 180.862-871; DOI: 10.1016/j.ajpath.2011.10.018)