Department of Immunology, West China School of Preclinical and Forensic Medicine, Chengdu, Sichuan University, Sichuan, China.
Cancer Sci. 2012 Feb;103(2):197-202. doi: 10.1111/j.1349-7006.2011.02122.x. Epub 2011 Nov 17.
Activation of CD40, a member of the tumor necrosis factor receptor (TNF-R) family, results in growth inhibition or apoptosis in some tumor cells, making CD40 a potential antitumor therapeutic target. Although it is known that CD40 is able to induce tumor necrosis factor-alpha (TNF-α) secretion and potentiate cisplatin's anticancer activity, whether TNF-α induction is involved in sensitizing cisplatin by CD40 has not been addressed. In this report, we provide evidence substantiating an important role of autocrine TNF-α in potentiation of cisplatin-induced apoptosis by recombinant soluble CD40 ligand (rsCD40L) in different human cancer cell lines. Activation of CD40 by rsCD40L induces two phases of autocrine TNF-α: the rapid early phase involving p38 MAP kinase and the robust and persistent late phase through enhanced tnf-α gene transcription. Blocking TNF-α with either a specific TNFR1 siRNA or a neutralizing anti-TNF-α antibody dramatically attenuated the potentiation effect of rsCD40L on cisplatin-induced cancer cell death. These results reveal an important role of TNF-α induction in CD40's chemosensitization activity and suggest that modulating TNF-α autocrine from cancer cells is an effective option for increasing the anticancer value of chemotherapeutics such as cisplatin.
CD40 的激活是肿瘤坏死因子受体（TNF-R）家族的成员之一，导致一些肿瘤细胞的生长抑制或凋亡，使 CD40 成为潜在的抗肿瘤治疗靶标。虽然已知 CD40 能够诱导肿瘤坏死因子-α（TNF-α）的分泌，并增强顺铂的抗癌活性，但 CD40 是否通过诱导 TNF-α来增敏顺铂尚未得到解决。在本报告中，我们提供了证据，证实了重组可溶性 CD40 配体（rsCD40L）通过 CD40 增敏顺铂诱导的不同人类癌细胞系中的细胞凋亡中，自分泌 TNF-α的重要作用。rsCD40L 通过 CD40 的激活诱导了 TNF-α 的两个自分泌阶段：快速早期阶段涉及 p38 MAP 激酶，而通过增强 tnf-α 基因转录的强而持久的晚期阶段。用特异性 TNFR1 siRNA 或中和抗 TNF-α 抗体阻断 TNF-α，显著减弱了 rsCD40L 对顺铂诱导的癌细胞死亡的增敏作用。这些结果揭示了 TNF-α诱导在 CD40 化学增敏活性中的重要作用，并表明调节来自癌细胞的 TNF-α 自分泌是增加顺铂等化疗药物抗癌价值的有效选择。
