Mechanism of Drug Resistance to First-Line Chemotherapeutics Mediated by TXNDC17 in Neuroblastomas.

Abstract

The prognosis of high-risk neuroblastomas (NB) that are resistant to first-line induction chemotherapy is relatively poor. This study explored the mechanism of resistance to first-line chemotherapeutics mediated by TXNDC17 and its potential solutions in NB. The genetic and clinical data of patients with NB were obtained from the Therapeutically Applicable Research to Generate Effective Treatments dataset. TXNDC17 and BECN1 expressions in NB cells were up- and downregulated by transfection with plasmids and shRNA, respectively. Autophagy-related proteins were detected by western blot. Cell viability was determined using cell proliferation and toxicity experiments. Apoptotic cells were detected using flow cytometry. Overall, 1076 pediatric and adolescent patients with NB were enrolled in this study. The 10-year overall survival (OS) rates and event-free survival (EFS) rates for the patients with a mutation of BECN1 were 37.4 ± 9.1% and 34.5 ± 8.8%, respectively. For patients with a mutation of TXNDC17, the 10-year OS and EFS were 41.4 ± 5.9% and 24.3 ± 5.1%, respectively, which were significantly lower than those in the unaltered group. The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance. Acquired resistance to first-line chemotherapeutics was associated with autophagy mediated by BECN1 and regulated by TXNDC17, which can be reversed by SAHA.