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 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.

METTL3 potentiates resistance to cisplatin through m6A modification of TFAP2C in seminoma

“…12,13 Previously, we showed that sensitivity of seminoma to CDDP is regulated by testis development-related gene 1 (TDRG1), which acts as an oncogene in testis. [14][15][16] Furthermore, this effect of TDRG1 on CDDP chemosensitivity has been found to be regulated by lncRNA H19 and miRNA-106b-5p. 15 Of note, tumour cells are often versatile in response to host microenvironment changes, such as high treatment burden.…”

Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives

“…Evidence is building on the contributory role of these mechanisms in several cancer models that acquire a resistance to cisplatin and deserve explorations in studies dedicated to TGCTs. Indeed, a recent study on TCam-2 cell lines (including an in vivo mouse model) showed that testis developmental related gene 1 ( TDRG1 ) promotes autophagy via the p110β/Rab5/Vps34 (PI3-kinase class III) cascade, contributing to cisplatin resistance [ 74 ]. Overall, and despite that specific studies for TGCTs are needed to confirm the relevance of these mechanisms, insights from other tumor models can be used as surrogates to pinpoint general mechanisms likely to be involved in cisplatin resistance ( Table S1 ).…”

Mir-483-3p, Mediated by KLF9, Functions as Tumor Suppressor in Testicular Seminoma via Targeting MMP9

“…Cells was cultured in DMEM medium + 10% fetal bovine serum along with penicillin (100 U/ml) and streptomycin (100 μg/ml, Invitrogen, Carlsbad, CA) at 37˚C with 5% CO 2 . Although Eppelmann et al demonstrated that the TCam-2 cell line was heterogenous, the cell line is still considered as an optimum seminoma cell model and extensively used in relevant studies [16][17][18].…”

“…MicroRNAs (miRNAs) are a class of endogenous small noncoding RNA molecules containing [18][19][20][21][22][23][24][25] nucleotides, which always function as post-transcriptional regulators of the mRNAs expression through binding to the 3′-untranslated region (3′-UTR) of their targets [8,9]. miRNAs have been found to be involved in a variety of biological processes, including tumor occurrence and progression [10,11].…”