ArticleActa pharmacologica Sinica2026
SOCS1 depletion drives osteosarcoma stemness and chemoresistance by suppressing ACTN4 degradation.
Article in Acta pharmacologica Sinica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- ADAMDEC-1 promotes atherosclerosis progression by interacting with ACTN4 and modulating the PTEN-PI3K/AKT signaling axis.Molecular and cellular biochemistry · 2026Article
- The effect of postoperative chemotherapy on survival outcomes and a nomogram for predicting overall survival in chondroblastic osteosarcoma.Scientific reports · 2025Article
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Authors and funding
13 authors.
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Abstract
Chemoresistance is a major factor contributing to the poor prognosis of osteosarcoma. Increasing evidence underscores the pivotal role of enhanced tumor stemness in driving drug resistance. In this study we investigated the molecular mechanisms underlying the chemoresistance and stemness in osteosarcoma. Two cisplatin-resistant osteosarcoma cell line models (U2OS-DDPr and 143B-DDPr) were established by culturing parental U2OS and 143B cells with escalating cisplatin concentrations (250 ng/mL to 2.5 µg/mL) over a 6-month period. We found that the expression levels of suppressor of cytokine signaling 1 (SOCS1), an E3 ubiquitin ligase, were markedly downregulated in both chemo-resistant osteosarcoma cells and osteosarcoma tumor specimens, and the reduced expression in tumor specimens was correlated to poor prognosis in osteosarcoma patients. Silencing SOCS1 significantly reduced cisplatin sensitivity, enhanced spheroid formation capacity, and upregulated the expression of stem cell markers including SOX2, OCT4, and CD44. Conversely, restoring SOCS1 expression reversed these effects both in vitro and in vivo. Immunoprecipitation-mass spectrometry analysis revealed that SOCS1 bound to ACTN4 and suppressed its protein expression by promoting K63-linked ubiquitination, ultimately leading to proteasomal degradation. Specifically, the SH2 domain of SOCS1 interacted with the N-terminal region of ACTN4, with Lys66 of ACTN4 playing a critical role in facilitating this interaction and subsequent ubiquitination. In addition, the expression of ACTN4 was highly enriched in chemo-resistant tissues, and its overexpression was positively associated with advanced tumor staging. Importantly, ACTN4 functioned as an oncogene to promote cisplatin resistance and stemness in osteosarcoma. Furthermore, we found that wortmannin, an inhibitor of ACTN4, could markedly block the effect of SOCS1 silencing on osteosarcoma aggressiveness. In conclusion, SOCS1 deletion promotes stemness and chemoresistance in osteosarcoma by inhibiting ACTN4 ubiquitination and degradation, which offers promising therapeutic targets for potentiating chemosensitivity in osteosarcoma.
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