TRIM8 anti-proliferative action against chemo-resistant renal cell carcinoma

// Mariano Francesco Caratozzolo 1,* , Alessio Valletti 2,* , Margherita Gigante 3 , Italia Aiello 4 , Francesca Mastropasqua 4 , Flaviana Marzano 1 , Pasquale Ditonno 5 , Giuseppe Carrieri 6 , Helene Simonnet 7 , Anna Maria D’Erchia 4 , Elena Ranieri 3 , Graziano Pesole 2,4 , Elisabetta Sbisa 1 and Apollonia Tullo 1 1 Institute for Biomedical Technologies ITB, Bari, Italy 2 Institute of Biomembranes and Bioenergetics IBBE, Bari, Italy 3 Dept Biomedical Science, University of Foggia, Foggia, Italy 4 Dept Biosciences, Biotechnologies and Biopharmaceutics, University of Bari “A. Moro”, Bari, Italy 5 Dept Emergency and Organ Transplantation DETO, University of Bari “A. Moro”, Bari, Italy 6 Dept Surgical Science, University of Foggia, Foggia, Italy 7 Centre de Recherche en Cancerologie de Lyon, Faculte de Medecine Lyon-Est, LYON Cedex 08 France * These authors contributed equally to this work Correspondence: Apollonia Tullo, email: // Keywords : ccRCC, drug resistance, TRIM8, cisplatin, nutlin 3, p53 Received : April 24, 2014 Accepted : June 6, 2014 Published : June 8, 2014 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.