Abstract
Ionizing radiation (IR) is a conventional cancer therapeutic, to which cancer cells develop radioresistance with exposure. The residual cancer cells after radiation treatment also have increased metastatic potential. The mechanisms by which cancer cells develop radioresistance and gain metastatic potential are still unknown. In this study acute IR exposure induced cancer cell senescence and apoptosis, but after long-term IR exposure, cancer cells exhibited radioresistance. The proliferation of radioresistant cells was retarded, and most cells were arrested in G0/G1 phase. The radioresistant cells simultaneously showed resistance to further IR-induced apoptosis, premature senescence, and epithelial to mesenchymal transformation (EMT). Acute IR exposure steadily elevated CDC6 protein levels due to the attenuation of ubiquitination, while CDC6 overexpression was observed in the radioresistant cells because the insufficiency of CDC6 phosphorylation blocked protein translocation from nucleus to cytoplasm, resulting in subcellular protein accumulation when the cells were arrested in G0/G1 phase. CDC6 ectopic overexpression in CNE2 cells resulted in apoptosis resistance, G0/G1 cell cycle arrest, premature senescence, and EMT, similar to the characteristics of radioresistant CNE2-R cells. Targeting CDC6 with siRNA promoted IR-induced senescence, sensitized cancer cells to IR-induced apoptosis, and reversed EMT. Furthermore, CDC6 depletion synergistically repressed the growth of CNE2-R xenografts when combined with IR. The study describes for the first time cell models for IR-induced senescence, apoptosis resistance, and EMT, three major mechanisms by which radioresistance develops. CDC6 is a novel radioresistance switch regulating senescence, apoptosis, and EMT. These studies suggest that CDC6highKI67low represents a new diagnostic marker of radiosensitivity, and CDC6 represents a new therapeutic target for cancer radiosensitization.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy in Southern China, Southeast Asia, and Africa, where its incidence is higher than in western countries [1]
We continuously monitored the expression of apoptosis- and senescence-associated molecules when cancer cells were exposed to Ionizing radiation (IR)
DNA damage intensified from 48 to 72 h, suggesting an unknown mechanism resulting in a second DNA damage. p53 and downstream molecule p21 protein levels were steadily elevated, p53 was activated over the time of IR exposure. p21 is closely associated with cell cycle arrest and cell senescence [19]
Summary
Ionizing radiation (IR) is a primary therapeutic approach for early NPC, which is usually highly radiosensitive, achieving a 5-year overall survival of 90 and 84% for stage I and IIA respectively [2]. Cancer cells in some patients with advanced disease develop radioresistance and increased metastatic potential, resulting in the treatment failure and tumor relapse [3]. There are few effective biomarkers available in the clinic for predicting tumor radiosensitivity [4]. IR directly induced DNA lesions and chromosome breaks, resulting in cell death [5]. Some cells developed radioresistance and escaped cell death. Recent studies indicated that stress-induced premature senescence and epithelial−mesenchymal transition (EMT) contribute to radioresistance [6, 7]. IR promoted invasion and metastasis by inducing EMT to bypass senescence [8, 9]
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