ArticleLaboratory investigation; a journal of technical methods and pathology2021
Activation of RSK2 upregulates SOX8 to promote methotrexate resistance in gestational trophoblastic neoplasia.
Article in Laboratory investigation; a journal of technical methods and pathology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 9 citations in OpenAlex.
- Targeting the GSK-3β/mTOR axis to overcome chemoresistance in gestational choriocarcinoma: molecular mechanisms and therapeutic opportunities.Cancer chemotherapy and pharmacology · 2026Review
- The Possible effect of Bosentan on the methotrexate-induced salivary gland changes in male rats: histological and Immunohistochemical study.Toxicology research · 2025Article
- Prognosticating gestational trophoblastic neoplasia: from FIGO 2000 to future models.EClinicalMedicine · 2024Review
- Promotive role of USP29-mediated deubiquitination in malignant proliferation of colorectal cancer cells via the KIAA1429/SOX8 axis.Biomolecules & biomedicine · 2023Article
- Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis.Cell death discovery · 2023Article
- Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.Nature communications · 2022Article
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Authors and funding
4 authors at 1 institution in 1 country.
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Abstract
Resistance to chemotherapy is frequently driven by aberrantly activated kinases in cancer. Herein, we characterized the global phosphoproteomic alterations associated with methotrexate (MTX) resistance in gestational trophoblastic neoplastic (GTN) cells. A total of 1111 phosphosites on 713 proteins were significantly changed, with highly elevated Ribosomal S6 Kinase 2 (RSK2) phosphorylation (pS227) observed in MTX-resistant GTN cells. Activation of RSK2 promoted cell proliferation and survival after MTX treatment in GTN cell models. Interestingly, RSK2 might play an important role in the regulation of reactive oxygen species (ROS) homeostasis, as manipulation of RSK2 activation affected ROS accumulation and SOX8 expression in GTN cells. In addition, overexpression of SOX8 partly rescued cell proliferation and survival in RSK2-depleted MTX-resistant GTN cells, suggesting that SOX8 might serve as a downstream effector of RSK2 to promote MTX resistance in GTN cells. Highly activated RSK2/SOX8 signaling was observed in MTX-resistant GTN specimens. Further, the RSK2 inhibitor BIX02565 effectively reduced SOX8 expression, induced ROS accumulation, and enhanced MTX-induced cytotoxicity in vitro and in vivo. Collectively, our findings suggested that RSK2 activation could promote MTX resistance via upregulating SOX8 and attenuating MTX-induced ROS in GTN cells, which may help to develop experimental therapeutics to treat MTX-resistant GTN.
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