2. Academic Validation
  3. BI-D1870 Induces Mitotic Dysfunction and Apoptosis in Neuroblastoma by Regulating the PI3K-Akt-mTORC1 Signal Axis

BI-D1870 Induces Mitotic Dysfunction and Apoptosis in Neuroblastoma by Regulating the PI3K-Akt-mTORC1 Signal Axis

  • Cancers (Basel). 2023 Mar 28;15(7):2023. doi: 10.3390/cancers15072023.
Liming Jin 1 2 3,  Tao Mi 1 2 3,  Xin Wu 1 2 3,  Zhang Wang 1 2 3,  Zhaoxia Zhang 1 2 3,  Jiayan Liu 1 2 3,  Zhaoying Wang 1 2 3,  Jinkui Wang 1 2 3,  Mujie Li 1 2 3,  Chunnian Ren 1 2 3,  Peng Guo 4,  Dawei He 1 2 3
Affiliations

Affiliations

  • 1 Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
  • 2 Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing 400014, China.
  • 3 China International Science and Technology Cooperation base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
  • 4 Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
PMID: 37046682 DOI: 10.3390/cancers15072023
Abstract

Introduction: Neuroblastoma (NB) is one of the most common extracranial solid malignant tumors in children. The 5-year survival rate of high-risk or refractory NB is less than 50%. Therefore, developing new effective therapeutics for NB remains an urgent challenge. Materials and Methods: Based on the NB dataset TARGET-NBL in the TCGA database, the prognosis-related genes were analyzed using univariate COX regression (p < 0.01). The protein network interaction of prognostic genes was analyzed using STRING to obtain 150 hub genes with HR > 1 and 150 hub genes with HR < 1. The Connectivity Map database was used to predict a therapeutic drug: BI-D1870, a ribosomal S6 kinase inhibitor. The inhibitory effect of BI-D1870 on NB was investigated through in vivo and in vitro experiments, and its inhibitory mechanism was explored. Results: Both the in vivo and in vitro experiments showed that BI-D1870 could inhibit tumor proliferation and induce tumor Apoptosis. Furthermore, we proved that BI-D1870 caused G2/M phase arrest and Mitosis damage in cells. RNA-seq of cells showed that BI-D1870 may inhibit the growth of NB by inhibiting the PI3K-Akt-mTOR axis. Western blot and immunofluorescence testing showed that BI-D1870 inhibited the PI3K-Akt-mTORC1 signal pathway to regulate the phosphorylation of RPS6 and 4E BP1 proteins, inhibit protein translation, and inhibit microtubule formation, thus preventing mitotic proliferation and inducing Apoptosis. Conclusions: This study provides strong support that BI-D1870 may be a potential Adjuvant therapy for NB.

Keywords

BI-D1870; G2/M arrest; RSK; mTORC1; neuroblastoma.

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