Increased MCL-1 synthesis promotes irradiation-induced nasopharyngeal carcinoma radioresistance via regulation of the ROS/AKT loop

• Published in: Cell death & disease Vol. 13; no. 2; pp. 131 - 10
• Main Authors: Liang, Ying-Ying, Niu, Fei-Yu, Xu, An-An, Jiang, Li-Li, Liu, Chun-shan, Liang, Hui-ping, Huang, Yu-Fan, Shao, Xun-Fan, Mo, Zhi-Wen, Yuan, Ya-Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.02.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 13/2; 13/31; 13/89; 14; 38/77; 38/90; 631/67/1059/485; 631/67/1536; 64/60; 692/308/1426; 82/1; 82/80; 96; AKT protein; Antibodies; Biochemistry; Biomedical and Life Sciences; Cancer therapies; Cell Biology; Cell Culture; Cell Line, Tumor; Head & neck cancer; Humans; Immunology; Intracellular signalling; Ionizing radiation; Kinases; Life Sciences; Malignancy; Mcl-1 protein; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Carcinoma - radiotherapy; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - radiotherapy; Phenotypes; Protein biosynthesis; Protein synthesis; Proteins; Proto-Oncogene Proteins c-akt; Radiation therapy; Radiation Tolerance - genetics; Radioresistance; Reactive Oxygen Species; Stem cells; Throat cancer
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04551-z

Worldwide, nasopharyngeal carcinoma (NPC) is a rare head and neck cancer; however, it is a common malignancy in southern China. Radiotherapy is the most important treatment strategy for NPC. However, although radiotherapy is a strong tool to kill cancer cells, paradoxically it also promotes aggressive phenotypes. Therefore, we mimicked the treatment process in NPC cells in vitro. Upon exposure to radiation, a subpopulation of NPC cells gradually developed resistance to radiation and displayed cancer stem-cell characteristics. Radiation-induced stemness largely depends on the accumulation of the antiapoptotic myeloid cell leukemia 1 (MCL-1) protein. Upregulated MCL-1 levels were caused by increased stability and more importantly, enhanced protein synthesis. We showed that repeated ionizing radiation resulted in persistently enhanced reactive oxygen species (ROS) production at a higher basal level, further promoting protein kinase B (AKT) signaling activation. Intracellular ROS and AKT activation form a positive feedback loop in the process of MCL-1 protein synthesis, which in turn induces stemness and radioresistance. AKT/MCL-1 axis inhibition attenuated radiation-induced resistance, providing a potential target to reverse radiation therapy-induced radioresistance.