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Testis developmental related gene 1 regulates the chemosensitivity of seminoma TCam-2 cells to cisplatin via autophagy.

ABSTRACT: 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 p110?/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 p110?/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 p110?/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.

SUBMITTER: Peng D

PROVIDER: S-EPMC6815826 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Testis developmental related gene 1 regulates the chemosensitivity of seminoma TCam-2 cells to cisplatin via autophagy.

Peng Dongyi D Wei Jingchao J Gan Yu Y Yang Jianfu J Jiang Xianzhen X Kitazawa Riko R Xiang Yali Y Dai Yingbo Y Tang Yuxin Y

Journal of cellular and molecular medicine 20190909 11

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 ...[more]

PMID: 31496041

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Project description:Testicular germ cell tumors (GCTs) are very common in young men and can be stratified into seminomas and non-seminomas. While seminomas share a similar gene expression and epigenetic profile with primordial germ cells, the stem cell population of the non-seminomas, the embryonal carcinoma (EC), resembles malignant embryonic stem cells. Thus, ECs are able to differentiate into cells of all three germ layers (teratomas) and even extra-embryonic-tissue-like cells (yolk-sac tumor, choriocarcinoma). In the last years, we demonstrated that the cellular microenvironment considerably influences the plasticity of seminomas (TCam-2 cells). Upon a microenvironment-triggered inhibition of the BMP signaling pathway in vivo (murine flank or brain), seminomatous TCam-2 cells reprogram to an EC-like cell fate. We identified SOX2 as a key factor activated upon BMP inhibition mediating the reprogramming process by regulating pluripotency, reprogramming and epigenetic factors. Indeed, CRISPR/Cas9 SOX2-deleted TCam-2 cells were able to maintain a seminoma-cell fate in vivo for about six weeks, but after six weeks in vivo still small sub-populations initiated differentiation. Closer analyses of these differentiated clusters suggested that the pioneer factor FOXA2 might be the driving force behind this induction of differentiation, since many FOXA2 interacting genes and differentiation factors like AFP, EOMES, CDX1, ALB, HAND1, DKK, DLK1, MSX1 and PITX2 were upregulated. In this study, we generated TCam-2 cells double-deficient for SOX2 and FOXA2 using the CRISPR/Cas9 technique and xenografted those cells into the flank of nude mice. Upon loss of SOX2 and FOXA2, TCam-2 maintained a seminoma cell fate for at least twelve weeks, demonstrating that both factors are key players in the reprogramming to an EC-like cell fate. Therefore, our study adds an important piece to the puzzle of GCT development and plasticity, providing interesting insights in what can be expected in a patient, when GCT cells are confronted with different microenvironments.

Dataset Information

Testis developmental related gene 1 regulates the chemosensitivity of seminoma TCam-2 cells to cisplatin via autophagy.

Publications

Testis developmental related gene 1 regulates the chemosensitivity of seminoma TCam-2 cells to cisplatin via autophagy.

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