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Anlotinib destabilizes PAX3-FOXO1 to induce rhabdomyosarcoma cell death via upregulating NEK2.
Song, Zian; Gong, Baocheng; Qu, Tongyuan; Chen, Yankun; Zhao, Guangzong; Jin, Yan; Zhao, Qiang.
Affiliation
  • Song Z; Department of Pediatric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
  • Gong B; Department of Pediatric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
  • Qu T; Department of Pediatric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
  • Chen Y; Department of Pediatric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
  • Zhao G; Department of Pediatric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
  • Jin Y; Department of Pediatric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: myyaner520@163.com.
  • Zhao Q; Department of Pediatric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: zhaoqiang@tjmuch.com.
Biomed Pharmacother ; 177: 117126, 2024 Aug.
Article in En | MEDLINE | ID: mdl-38996706
ABSTRACT

BACKGROUND:

Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children and adolescents, in which PAX3-FOXO1 fusion gene positive patients have very poor prognosis. PAX3-FOXO1 has been identified as an independent prognostic predictor in RMS, with no currently available targeted therapeutic intervention. The novel tyrosine kinase inhibitor anlotinib exhibits a wide range of anticancer effects in multiple types of cancers; however, there have been no relevant studies regarding its application in RMS. MATERIALS AND

METHODS:

We investigated the effects of PAX3-FOXO1 on the therapeutic efficacy of anlotinib using the CCK-8 assay, flow cytometry, invasion assay, wound healing assay, western blotting, quantitative polymerase chain reaction(qPCR), and xenograft experiments. RNA-seq and co-immunoprecipitation assays were conducted to determine the specific mechanism by which anlotinib regulates PAX3-FOXO1 expression.

RESULTS:

Anlotinib effectively inhibited RMS cell proliferation and promoted apoptosis and G2/M phase arrest while impeding tumor growth in vivo. Downregulation of PAX3-FOXO1 enhances the antitumor effects of anlotinib. Anlotinib upregulates protein kinase NEK2 and increases the degradation of PAX3-FOXO1 via the ubiquitin-proteasome pathway, leading to a reduction in PAX3-FOXO1 protein levels.

CONCLUSION:

Anlotinib effectively inhibited the malignant progression of RMS and promoted degradation of the fusion protein PAX3-FOXO1. Anlotinib could be a targeted therapeutic approach to treat PAX3-FOXO1 fusion-positive RMS.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Quinolines / Rhabdomyosarcoma / Oncogene Proteins, Fusion / Up-Regulation / Apoptosis / Cell Proliferation / NIMA-Related Kinases / Indoles Limits: Animals / Humans Language: En Journal: Biomed Pharmacother Year: 2024 Type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Quinolines / Rhabdomyosarcoma / Oncogene Proteins, Fusion / Up-Regulation / Apoptosis / Cell Proliferation / NIMA-Related Kinases / Indoles Limits: Animals / Humans Language: En Journal: Biomed Pharmacother Year: 2024 Type: Article