Wu I-Jung, Lin Rong-Jaan, Wang Hsin-Chiao, Yuan Tein-Ming, Chuang Show-Mei
College of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan; Taichung Hospital, Ministry of Health and Welfare, Taichung 40343, Taiwan.
Bachelor Program of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan.
Arch Biochem Biophys. 2017 May 15;622:26-35. doi: 10.1016/j.abb.2017.04.008. Epub 2017 Apr 23.
TRIB3, which is a pseudokinase known to regulate multiple pro-survival pathways, appears to be a potential therapeutic target for the treatment of human tumors. However, its precise role in cancer is controversial, as TRIB3 protein levels have been associated with both good and poor prognosis in cancer patients. Here, we investigated the significance of TRIB3 expression in the survival of gastric cancer cells exposed to anticancer drugs. We found that the tested anticancer drug, doxorubicin, induced cytotoxicity by decreasing TRIB3 transcription, which was followed by apoptotic cell death. Moreover, TRIB3 siRNA knockdown appeared to enhance doxorubicin-induced apoptosis in gastric cancer cells, concurrently with altering the expression of downstream apoptotic factors. Conversely, overexpression of TRIB3 significantly protected cells against doxorubicin-induced apoptosis. Our results indicate that downregulation of TRIB3 appears to promote cell death and enhance doxorubicin-induced apoptosis, supporting the anti-apoptotic role of TRIB3. The inductions of three classes of MAPKs failed to affect doxorubicin-mediated TRIB3 downregulation, while TRIB3 overexpression did not affect doxorubicin-induced MAPK activation. In sum, our findings indicate that TRIB3 plays an anti-apoptotic role in doxorubicin-treated gastric cancer cell lines, perhaps indicating that the status of TRIB3 expression in response to anticancer drugs, such as doxorubicin, irinotecan or oxaliplatin, may reflect the efficiency for cancer therapy.
TRIB3是一种已知可调节多种促生存途径的假激酶，似乎是治疗人类肿瘤的一个潜在治疗靶点。然而，其在癌症中的精确作用存在争议，因为TRIB3蛋白水平与癌症患者的预后好坏均有关联。在此，我们研究了TRIB3表达在暴露于抗癌药物的胃癌细胞存活中的意义。我们发现，所测试的抗癌药物阿霉素通过降低TRIB3转录诱导细胞毒性，随后导致凋亡性细胞死亡。此外，TRIB3 siRNA敲低似乎增强了阿霉素诱导的胃癌细胞凋亡，同时改变了下游凋亡因子的表达。相反，TRIB3的过表达显著保护细胞免受阿霉素诱导的凋亡。我们的结果表明，TRIB3的下调似乎促进细胞死亡并增强阿霉素诱导的凋亡，支持了TRIB3的抗凋亡作用。三类丝裂原活化蛋白激酶（MAPKs）的诱导未能影响阿霉素介导的TRIB3下调，而TRIB3过表达并未影响阿霉素诱导的MAPK激活。总之，我们的研究结果表明，TRIB3在阿霉素处理的胃癌细胞系中发挥抗凋亡作用，这可能表明TRIB3在响应阿霉素、伊立替康或奥沙利铂等抗癌药物时的表达状态可能反映癌症治疗的疗效。
