Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China.
Department of Urology, Xiangya Hospital of Central South University, Changsha, China.
J Cell Mol Med. 2019 Nov;23(11):7773-7784. doi: 10.1111/jcmm.14654. Epub 2019 Sep 9.
We previously identified testis developmental related gene 1 (TDRG1), a gene implicated in proliferation of TCam-2 seminoma cells. Recent evidence has revealed that autophagy influences the chemosensitivity of cancer cells to chemotherapy. However, whether TDRG1 protein regulates autophagy in seminoma cells and influences their sensitivity to cis-dichlorodiammine platinum (CDDP) remains unknown. In this study, we used TCam-2 cells and male athymic BALB/c nude mice with xenografts of TCam-2 cells to investigate autophagy, cell viability, apoptosis and the p110β/Rab5/Vps34 (PI3-kinase Class III) pathway under the conditions of TDRG1 overexpression or knockdown and with or without CDDP treatment. We found that TDRG1 upregulation promoted autophagy in both TCam-2 cells and seminoma xenografts via p110β/Rab5/Vps34 activation. Inhibition of autophagy reduced cell viability and promoted apoptosis during CDDP treatment of TCam-2 cells. Similarly, TDRG1 knockdown inhibited autophagy, reduced cell viability and promoted apoptosis during CDDP treatment of TCam-2 cells. TDRG1 knockdown inhibited tumour growth and promoted apoptosis in TCam-2 cell xenografts, whereas TDRG1 overexpression had the opposite effect. According to these results, we propose that high expression of TDRG1 promotes autophagy through the p110β/Rab5/Vps34 pathway in TCam-2 cells. TDRG1 overexpression promotes autophagy and leads to CDDP resistance, whereas TDRG1 knockdown inhibits autophagy and promotes chemosensitivity to CDDP both in vivo and in vitro. This study has uncovered a novel role of TDRG1 in reducing chemoresistance during CDDP treatment and provides potential therapeutic strategies for the treatment of human seminoma.
我们之前发现睾丸发育相关基因 1（TDRG1），该基因与 TCam-2 精原细胞瘤细胞的增殖有关。最近的证据表明，自噬会影响癌细胞对化疗的敏感性。然而，TDRG1 蛋白是否调节精原细胞瘤细胞中的自噬并影响它们对顺铂（CDDP）的敏感性尚不清楚。在这项研究中，我们使用 TCam-2 细胞和雄性无胸腺 BALB/c 裸鼠，用 TCam-2 细胞的异种移植来研究自噬、细胞活力、细胞凋亡以及 TDRG1 过表达或敲低时以及有或没有 CDDP 处理时的 p110β/Rab5/Vps34（PI3-激酶 III 类）途径。我们发现，TDRG1 的上调通过 p110β/Rab5/Vps34 的激活促进了 TCam-2 细胞和精原细胞瘤异种移植中的自噬。在 TCam-2 细胞用 CDDP 处理时，抑制自噬会降低细胞活力并促进细胞凋亡。同样，TDRG1 的敲低抑制自噬，降低细胞活力并促进 TCam-2 细胞用 CDDP 处理时的细胞凋亡。TDRG1 的敲低抑制 TCam-2 细胞异种移植中的肿瘤生长并促进细胞凋亡，而 TDRG1 的过表达则产生相反的效果。根据这些结果，我们提出 TDRG1 通过 p110β/Rab5/Vps34 途径在 TCam-2 细胞中促进自噬，高表达 TDRG1 通过 p110β/Rab5/Vps34 途径促进自噬并导致 CDDP 耐药，而 TDRG1 的敲低抑制自噬并促进 CDDP 耐药。在体内和体外都提高了对 CDDP 的敏感性。这项研究揭示了 TDRG1 在降低 CDDP 治疗期间化疗耐药性方面的新作用，并为治疗人类精原细胞瘤提供了潜在的治疗策略。
