Suppression of the cuproptosis mechanism by the oncogene RASGRP2 in driving osteosarcoma progression
Year: 2026
Type: article
Abstract: Background: Osteosarcoma remains a life-threatening malignancy with poor outcomes in patients, who may experience metastatic disease even with multiagent chemotherapy. Cuproptosis, a recently discovered copper-dependent cell death mechanism, represents a potential therapeutically relevant vulnerability in cancer. However, the mechanisms underlying cuproptosis resistance in osteosarcoma have not been clarified, and whether oncogenic pathways enable tumor cells to evade cuproptotic death remain unknown. This study aims to investigate the functional role of the oncogene RASGRP2 in osteosarcoma progression and to determine whether RASGRP2 suppresses the cuproptosis mechanism and thereby confers resistance to copper-induced cell death.Methods: We investigated RASGRP2 expression in osteosarcoma tumors and cell lines using public datasets and laboratory assays. In functional studies, small interfering RNA (siRNA) knockdown and lentiviral overexpression were used to assess cell proliferation, colony formation, and tumor growth in xenograft models. In mechanistic studies, cuproptosis-related gene expression, intracellular copper accumulation, and sensitivity to elesclomol-copper treatment were examined through real-time quantitative polymerase chain reaction, Western blotting, copper assays, and viability assays.Results: RASGRP2 was significantly upregulated in osteosarcoma tissues and cell lines, with high expression correlating with poor overall survival and disease-free survival. RASGRP2 knockdown suppressed cell proliferation and colony formation in vitro, while overexpression promoted tumor growth in vivo. Bioinformatic analysis revealed inverse correlations between RASGRP2 and key cuproptosis mediators (FDX1, DLAT, ATP7B, LIAS, and DLD). RASGRP2 depletion upregulated these cuproptosis genes at the messenger RNA and protein levels, increased intracellular copper accumulation, and sensitized osteosarcoma cells to elesclomol-copper-induced cell death both in vitro and in colony formation assays.Conclusions: RASGRP2 functions as a critical oncogenic driver in osteosarcoma that confers resistance to cuproptosis by suppressing key cuproptosis machinery. These findings establish the RASGRP2-cuproptosis axis as a novel therapeutic target and suggest that combining RASGRP2 inhibition with copper ionophore therapy may represent a promising strategy for treating this aggressive malignancy.
Source: Translational Cancer Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7224111936