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  2. Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer

Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer

  • J Transl Med. 2024 Feb 3;22(1):133. doi: 10.1186/s12967-024-04934-0.
Yuting Huang # 1 2 Szehoi Chan # 3 Shuna Chen 3 Xueqi Liu 3 Miao Li 4 Liyuan Zheng 5 Zhaoxia Dong 3 Ziyi Yang 3 Zixuan Liu 3 Disheng Zhou 3 Xingding Zhang 6 Bo Zhang 7 8
Affiliations

Affiliations

  • 1 Department of Interventional Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 2 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 3 Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China.
  • 4 Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 5 Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.
  • 6 Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China. zhangxd39@mail.sysu.edu.
  • 7 Department of Interventional Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. zhangb28@mail.sysu.edu.cn.
  • 8 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. zhangb28@mail.sysu.edu.cn.
  • # Contributed equally.
Abstract

Background: Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal Cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced Apoptosis of CRC.

Methods: An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5'-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell Apoptosis in vivo and in vitro.

Results: Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced Apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell Apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell Apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP.

Conclusions: IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.

Keywords

Apoptosis; Colorectal cancer; IMPDH2; Oxaliplatin resistance; Purine metabolism; β‑catenin.

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