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CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming
Mengxuan Li1, Nan Che2, Yu Jin1
1Human Anatomy and Histoembryology, Yanbian University College of Medicine, Yanji, People's Republic of China.
Background:
Aerobic glycolysis plays an important role in bladder cancer (BLCA) progression and chemoresistance. Cyclin-dependent kinase inhibitor-3 (CDKN3), a dual-specificity protein tyrosine phosphatase, has aberrant upregulation in multiple cancer types and is associated with tumorigenesis. However, the role of CDKN3 in BLCA progression and glycolysis has not been elucidated.
Purpose:
In this study, we investigated the effect and underlying mechanisms of CDKN3 on bladder cancer chemoresistance.
Results:
This study confirmed that CDKN3 was overexpressed in BLCA tissues and promoted proliferation and migration. Additionally, our results showed a CDKN3-dependent mechanism on chemoresistance; chemoresistance cells were transformed into chemosensitivity cells by CDKN3 knockdown. Additionally, we showed that CDKN3 knockdown decreased glycolysis by inhibiting LDHA expression in BLCA chemoresistance cells. The results also proved that LDHA was an important mediator of CDKN3-regulated BLCA resistance. LDHA overexpression reversed glycolysis inhibition and chemosensitivity induced by CDKN3 downregulation.
Conclusion:
These data collectively identified a vital role of CDKN3 in glycolysis and chemoresistance by regulating LDHA expression in BLCA cells, providing a possible therapeutic strategy for treating BLCA.
Insights
Cyclin-dependent kinase inhibitor-3 (CDKN3) promotes bladder cancer (BLCA) progression and chemoresistance by increasing glycolysis via LDHA. Reducing CDKN3 may offer a new therapeutic strategy for BLCA treatment.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Aerobic glycolysis is crucial for bladder cancer (BLCA) progression and chemoresistance.
- Cyclin-dependent kinase inhibitor-3 (CDKN3) is upregulated in various cancers, but its role in BLCA and glycolysis remains unclear.
Purpose of the Study:
- To investigate the role and mechanisms of CDKN3 in bladder cancer chemoresistance.
- To elucidate the relationship between CDKN3, glycolysis, and chemoresistance in BLCA.
Main Methods:
- Assessed CDKN3 expression in BLCA tissues.
- Investigated the effects of CDKN3 knockdown on BLCA cell proliferation, migration, and chemoresistance.
- Analyzed the impact of CDKN3 on glycolysis and lactate dehydrogenase A (LDHA) expression.
- Evaluated the role of LDHA as a mediator in CDKN3-regulated chemoresistance.
Main Results:
- CDKN3 was overexpressed in BLCA tissues, promoting proliferation and migration.
- CDKN3 knockdown sensitized BLCA cells to chemotherapy and reduced glycolysis.
- CDKN3 regulated glycolysis by inhibiting LDHA expression.
- LDHA overexpression reversed the effects of CDKN3 downregulation on glycolysis and chemosensitivity.
Conclusions:
- CDKN3 plays a critical role in bladder cancer glycolysis and chemoresistance by regulating LDHA expression.
- Targeting CDKN3 and its downstream effector LDHA presents a potential therapeutic strategy for BLCA.
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