Radiation-promoted CDC6 protein stability contributes to radioresistance by regulating senescence and epithelial to mesenchymal transition.

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.

• Authors: Xiaohui Yu, Youhong Liu, Linglong Yin, Yongbo Peng, Yuchong Peng, Yingxue Gao, Bowen Yuan, Qianling Zhu, Tuoyu Cao, Bowen Xie, Lunquan Sun, Yan Chen, Zhicheng Gong, Yuanzheng Qiu, Xuegong Fan, Xiong Li
• Journal: Oncogene (Oncogene) Vol. 38 Issue 4 Pg. 549-563 (01 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30158672 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Differentiation, T-Lymphocyte
• CD6 antigen
• Ki-67 Antigen
• MKI67 protein, human
• Neoplasm Proteins
• RNA, Small Interfering

Topics

• Animals
• Antigens, CD (biosynthesis, genetics, physiology)
• Antigens, Differentiation, T-Lymphocyte (biosynthesis, genetics, physiology)
• Apoptosis (radiation effects)
• Carcinoma (pathology, radiotherapy)
• Cell Cycle Checkpoints (radiation effects)
• Cell Line, Tumor
• Cellular Senescence (physiology)
• Epithelial-Mesenchymal Transition (radiation effects)
• Heterografts
• Humans
• Ki-67 Antigen (biosynthesis)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nasopharyngeal Neoplasms (pathology, radiotherapy)
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• Phosphorylation (radiation effects)
• Protein Processing, Post-Translational (radiation effects)
• Protein Stability
• Protein Transport (radiation effects)
• RNA Interference
• RNA, Small Interfering (genetics)
• Radiation Tolerance (physiology)
• Ubiquitination (radiation effects)
• X-Rays