Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
Cell Death Dis. 2023 Feb 10;14(2):102. doi: 10.1038/s41419-023-05637-y.
The E3 ligase TNF receptor-associated factor 4 (TRAF4) is upregulated and closely associated with tumorigenesis and the progression of multiple human malignancies. However, its effect on radiosensitivity in colorectal cancer (CRC) has not been elucidated. The present study found that TRAF4 was significantly increased in CRC clinical tumor samples. Depletion of TRAF4 impaired the malignant phenotype of CRC cells and sensitized irradiation-induced cell death. Irradiation activated the c-Jun N-terminal kinases (JNKs)/c-Jun signaling via increasing JNKs K63-linked ubiquitination and phosphorylation. Furthermore, c-Jun activation triggered the transcription of the antiapoptotic protein Bcl-xL, thus contributing to the radioresistance of CRC cells. TRAF4 was positively correlated with c-Jun and Bcl-xL, and blocking TRAF4 or inhibiting Bcl-xL with inhibitor markedly promoted ionizing radiation (IR)-induced intrinsic apoptosis and sensitized CRC cells to radiotherapy in vitro and in vivo. Our findings illustrate a potential mechanism of radioresistance, emphasizing the clinical value of targeting the TRAF4/Bcl-xL axis in CRC therapy.
E3 连接酶 TNF 受体相关因子 4（TRAF4）上调，并与多种人类恶性肿瘤的发生和进展密切相关。然而，其对结直肠癌（CRC）放射敏感性的影响尚未阐明。本研究发现 TRAF4 在 CRC 临床肿瘤样本中显著增加。TRAF4 的耗竭削弱了 CRC 细胞的恶性表型，并敏化了照射诱导的细胞死亡。照射通过增加 JNKs K63 连接的泛素化和磷酸化来激活 c-Jun N 末端激酶（JNKs）/c-Jun 信号通路。此外，c-Jun 的激活触发了抗凋亡蛋白 Bcl-xL 的转录，从而导致 CRC 细胞的放射抵抗。TRAF4 与 c-Jun 和 Bcl-xL 呈正相关，用抑制剂阻断 TRAF4 或抑制 Bcl-xL 可显著促进电离辐射（IR）诱导的内在凋亡，并在体外和体内使 CRC 细胞对放射治疗敏感。我们的研究结果说明了放射抵抗的潜在机制，强调了针对 TRAF4/Bcl-xL 轴在 CRC 治疗中的临床价值。
