Targeting the WWP2-ASPP2 axis overcomes cisplatin resistance by inhibiting the mevalonate pathway in TP53-mutant
Qixiang Fang1, Chengyu You1, Xi Xiao1
1Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China; Gansu Province Clinical Research Center for Urinary System Diseases, The Second Hospital of Lanzhou University, Lanzhou, Gansu, 730030, China.
Abstract:
Cisplatin resistance remains a major challenge in bladder cancer. Although the tumor suppressor ASPP2 is a critical co-factor for TP53-mediated apoptosis, its role in metabolic reprogramming and cisplatin response remains unclear. This study aimed to delineate the mechanism by which ASPP2 regulates cisplatin sensitivity through metabolic reprogramming. We first assessed the clinical significance of ASPP2 using patient tissues and public databases, finding that its downregulation in bladder cancer is associated with poor patient survival. Through gain- and loss-of-function studies in vitro and in vivo, we further demonstrated that ASPP2 inhibits the mevalonate (MVA) pathway independently of TP53 status, thereby sensitizing cells to cisplatin-induced DNA damage and apoptosis. This chemosensitizing effect was specifically reversed by the addition of MVA pathway metabolites. Moreover, WWP2 was identified as the E3 ubiquitin ligase responsible for ASPP2 degradation via K48-linked ubiquitination. Finally, WWP2 silencing was shown to stabilize ASPP2, suppress the MVA pathway, and synergize with cisplatin to impede tumor growth in mouse models. Overall, the WWP2-ASPP2-MVA pathway axis is identified as a novel driver of cisplatin resistance in bladder cancer. These results establish a mechanistic basis for targeting this axis to restore chemosensitivity, offering a promising therapeutic strategy for recalcitrant disease.
Insights
The tumor suppressor ASPP2 inhibits the mevalonate pathway, enhancing cisplatin sensitivity in bladder cancer. Targeting the WWP2-ASPP2-MVA axis may overcome drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Cisplatin resistance is a significant hurdle in bladder cancer treatment.
- The role of tumor suppressor ASPP2 in metabolic reprogramming and cisplatin response is not well understood.
- ASPP2 is a known co-factor for TP53-mediated apoptosis.
Purpose of the Study:
- To investigate the mechanism by which ASPP2 influences cisplatin sensitivity through metabolic reprogramming in bladder cancer.
- To identify the molecular players involved in ASPP2 regulation and its impact on the mevalonate pathway.
Main Methods:
- Analysis of clinical patient tissues and public databases for ASPP2 significance.
- In vitro and in vivo gain- and loss-of-function studies.
- Identification of WWP2 as the E3 ubiquitin ligase targeting ASPP2.
- Assessment of mevalonate pathway metabolites and their effect on chemosensitivity.
Main Results:
- Downregulation of ASPP2 in bladder cancer correlates with poor patient survival.
- ASPP2 inhibits the mevalonate (MVA) pathway, independent of TP53, sensitizing cells to cisplatin.
- MVA pathway metabolites reversed the chemosensitizing effect of ASPP2.
- WWP2 targets ASPP2 for degradation; WWP2 silencing stabilizes ASPP2 and suppresses the MVA pathway.
- WWP2 silencing synergized with cisplatin to inhibit tumor growth in mouse models.
Conclusions:
- The WWP2-ASPP2-MVA pathway axis is a novel determinant of cisplatin resistance in bladder cancer.
- Targeting this axis offers a potential therapeutic strategy to restore chemosensitivity in resistant bladder cancer.
- ASPP2's role in metabolic reprogramming is crucial for its function in chemosensitization.
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