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Published on: February 9, 2016
TRIM8 anti-proliferative action against chemo-resistant renal cell carcinoma
Mariano Francesco Caratozzolo1, Alessio Valletti2, Margherita Gigante3
1Institute for Biomedical Technologies ITB, Bari, Italy. Contributed equally to this work.
Abstract:
In some tumours, despite a wild-type p53 gene, the p53 pathway is inactivated by alterations in its regulators or by unknown mechanisms, leading to resistance to cytotoxic therapies. Understanding the mechanisms of functional inactivation of wild-type p53 in these tumours may help to define prospective targets for treating cancer by restoring p53 activity. Recently, we identified TRIM8 as a new p53 modulator, which stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation. In this paper we demonstrated that TRIM8 deficit dramatically impairs p53-mediated cellular responses to chemotherapeutic drugs and that TRIM8 is down regulated in patients affected by clear cell Renal Cell Carcinoma (ccRCC), an aggressive drug-resistant cancer showing wild-type p53. These results suggest that down regulation of TRIM8 might be an alternative way to suppress p53 activity in RCC. Interestingly, we show that TRIM8 expression recovery in RCC cell lines renders these cells sensitive to chemotherapeutic treatments following p53 pathway re-activation. These findings provide the first mechanistic link between TRIM8 and the drug resistance of ccRCC and suggest more generally that TRIM8 could be used as enhancer of the chemotherapy efficacy in cancers where p53 is wild-type and its pathway is defective.
Insights
Defective p53 pathway signaling, despite a wild-type p53 gene, contributes to cancer drug resistance. Restoring TRIM8 expression reactivates the p53 pathway, enhancing chemotherapy efficacy in clear cell renal cell carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The p53 pathway is crucial for tumor suppression but can be functionally inactivated in cancers with wild-type p53 genes, leading to chemoresistance.
- Understanding these inactivation mechanisms is vital for developing novel cancer treatment strategies that restore p53 activity.
- Tripartite motif-containing protein 8 (TRIM8) has been identified as a novel p53 modulator that stabilizes p53.
Purpose of the Study:
- To investigate the role of TRIM8 in the functional inactivation of the p53 pathway in drug-resistant cancers.
- To explore the potential of TRIM8 as a therapeutic target for enhancing chemotherapy efficacy.
Main Methods:
- Assessed the impact of TRIM8 deficiency on p53-mediated cellular responses to chemotherapeutic drugs.
- Examined TRIM8 expression levels in patients with clear cell renal cell carcinoma (ccRCC).
- Investigated the effect of TRIM8 expression recovery on the sensitivity of ccRCC cell lines to chemotherapy.
Main Results:
- TRIM8 deficit significantly impairs p53-mediated responses to chemotherapeutic agents.
- TRIM8 is downregulated in ccRCC, a drug-resistant cancer with wild-type p53.
- Restoring TRIM8 expression in ccRCC cells re-activates the p53 pathway and restores sensitivity to chemotherapy.
Conclusions:
- Downregulation of TRIM8 is a potential mechanism for p53 pathway suppression in renal cell carcinoma.
- TRIM8 expression recovery can enhance chemotherapy efficacy in ccRCC by re-activating the p53 pathway.
- TRIM8 represents a promising therapeutic target for improving chemotherapy outcomes in cancers with wild-type p53 and defective p53 pathway signaling.
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