The NUPR1/p73 axis contributes to sorafenib resistance in hepatocellular carcinoma. (28th October 2021)

• Record Type: Journal Article
• Authors: Augello, Giuseppa; Emma, Maria Rita; Azzolina, Antonina; Puleio, Roberto; Condorelli, Lucia; Cusimano, Antonella; Giannitrapani, Lydia; McCubrey, James A.; Iovanna, Juan Lucio; Cervello, Melchiorre
• Is Part Of: Cancer letters. Volume 519(2021)
• Page Start: 250
• Page End: 262
• Publication Date: 2021-10-28
• Subjects: Hepatocellular carcinoma -- NUPR1 -- p73 -- NSC5994 -- Autophagy -- Apoptosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.07.026
• Languages: English
• ISSNs: 0304-3835

Abstract

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 p7 3 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. Graphical abstract: Image 1 Highlights: There is a pressing demand for new and more effective therapies for the treatment of HCC. NUPR1 plays an essential role in controlling cell viability and sorafenib resistance in HCC. p73 is responsible for sensitizing NUPR1 knock-down cells to sorafenib. The small-molecule NSC59984 has anti-tumor effects against HCC via p73 activation. The combination of sorafenib with NSC59984 synergistically inhibited HCC tumor growth both in vitro and in vivo.