Department of Biology, College of Arts and Sciences, Central Mindanao University, Musuan, Philippines.
School of Pharmacy (School of Wine), Binzhou Medical University, Binzhou, China.
J Interferon Cytokine Res. 2023 Nov;43(11):495-511. doi: 10.1089/jir.2023.0088. Epub 2023 Oct 31.
Interleukin-6 (IL-6) can promote cell proliferation in prostate cancer (PCa). Full-length transient receptor potential melastatin 2 (TRPM2-L) is highly expressed in PCa. However, the association between IL-6 and TRPM2-L in PCa is unclear. Here, human PCa cell lines, PC-3 and DU-145, were treated with 10 μg/mL tocilizumab, an IL-6 receptor (IL-6R) inhibitor, and the TRPM2-L protein expression in cells was significantly decreased. Cells were stably transfected with TRPM2 short-interfering RNA (siRNA) and cell survival clearly declined. Recombinant IL-6 treatment weakened the effects of TRPM2-siRNA on cell survival. TRPM2-L binds directly to IL-6R in PC-3 and DU-145 cells. The protein expression of hypoxia-inducible factor-1α was suppressed by reduction with TRPM2-L in PC-3 and DU-145 cells. Human umbilical vein endothelial cells (HUVECs) were indirectly cocultured with PCa cells, and the invasion and angiogenic activity of HUVECs were enhanced after coculture with PCa cells. However, TRPM2-L reduction in PCa cells significantly decreased the invasion and angiogenic activity of HUVECs compared to the control coculture. , xenograft tumors were induced using PC-3 cells. Tocilizumab treatment or TRPM2-L reduction clearly suppressed tumor growth. Meanwhile, the injection of mouse recombinant IL-6 weakened the antitumor effects of TRPM2-L reduction. These data demonstrate that the IL-6/TRPM2-L axis in PCa tumor growth is important, and interference of the IL-6/TRPM2-L axis may be a novel approach for PCa therapy.
白细胞介素-6（IL-6）可促进前列腺癌（PCa）中的细胞增殖。全长瞬时受体电位 melastatin 2（TRPM2-L）在 PCa 中高度表达。然而，IL-6 与 PCa 中的 TRPM2-L 之间的关联尚不清楚。在这里，用 10μg/ml 的托珠单抗（一种 IL-6 受体（IL-6R）抑制剂）处理人 PCa 细胞系 PC-3 和 DU-145，细胞中的 TRPM2-L 蛋白表达明显下降。细胞用 TRPM2 短发夹 RNA（siRNA）稳定转染，细胞存活率明显下降。重组 IL-6 处理削弱了 TRPM2-siRNA 对细胞存活的影响。TRPM2-L 在 PC-3 和 DU-145 细胞中直接与 IL-6R 结合。在 PC-3 和 DU-145 细胞中，通过降低 TRPM2-L 的表达，抑制缺氧诱导因子-1α的蛋白表达。人脐静脉内皮细胞（HUVECs）与 PCa 细胞间接共培养，与 PCa 细胞共培养后，HUVECs 的侵袭和血管生成活性增强。然而，与对照共培养相比，PCa 细胞中 TRPM2-L 的减少显著降低了 HUVECs 的侵袭和血管生成活性。使用 PC-3 细胞诱导异种移植瘤。托珠单抗治疗或 TRPM2-L 减少明显抑制肿瘤生长。同时，注射小鼠重组 IL-6 削弱了 TRPM2-L 减少的抗肿瘤作用。这些数据表明，PCa 肿瘤生长中的 IL-6/TRPM2-L 轴很重要，干扰 IL-6/TRPM2-L 轴可能是 PCa 治疗的一种新方法。
