The NUPR1/p73 axis contributes to sorafenib resistance in hepatocellular carcinoma

Maria Rita Emma, Lydia Giannitrapani, Melchiorre Cervello, Giuseppa Augello, Maria Rita Emma, Roberto Puleio, Lydia Giannitrapani, Antonina Azzolina, Lucia Condorelli, Antonella Cusimano, James A. Mccubrey, Juan Lucio Iovanna, Antonella Cusimano, Giuseppa Augello

Risultato della ricerca: Articlepeer review

Abstract

The multikinase inhibitor sorafenib was the first drug approved by the FDA for treating patients with advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a major challenge for improving the effectiveness of HCC treatment. Previously, we identified several genes modulated after sorafenib treatment of human HCC cells, including the stress-inducible nuclear protein 1 (NUPR1) gene. Multiple studies have shown that NUPR1 regulates autophagy, apoptosis, and chemoresistance. Here, we demonstrate that treatment of HCC cells with sorafenib resulted in the activation of autophagic flux. NUPR1 knock-down (KD) in HCC cells was associated with increased p62 expression, suggesting an impairment of autophagic flux, and with a significant increase of cell sensitivity to sorafenib. In NUPR1 KD cells, reduced levels of NUPR1 were associated with the increased expression of p73 as well as its downstream transcription targets PUMA, NOXA, and p21. Simultaneous silencing of p73 and NUPR1 in HCC cells resulted in increased resistance to sorafenib, as compared to the single KD of either gene. Conversely, pharmacological activation of p73, via the novel p73 small molecule activator NSC59984, determined synergistic anti-tumor effects in sorafenib-treated HCC cells. The combination of NSC59984 and sorafenib, when compared to either treatment alone, synergistically suppressed tumor growth of HCC cells in vivo. Our data suggest that the activation of the p73 pathway achieved by NUPR1 KD potentiates sorafenib-induced anti-tumor effects in HCC cells. Moreover, combined pharmacological therapy with the p73 activator NSC59984 and sorafenib could represent a novel approach for HCC treatment.
Lingua originaleEnglish
pagine (da-a)250-262
Numero di pagine13
RivistaCancer Letters
Volume519
Stato di pubblicazionePublished - 2021

All Science Journal Classification (ASJC) codes

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  • ???subjectarea.asjc.1300.1306???

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