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

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 a...

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Bibliographic Details
Published in:Cancer letters 2021-10, Vol.519, p.250-262
Main Authors: Augello, Giuseppa, Emma, Maria Rita, Azzolina, Antonina, Puleio, Roberto, Condorelli, Lucia, Cusimano, Antonella, Giannitrapani, Lydia, McCubrey, James A., Iovanna, Juan Lucio, Cervello, Melchiorre
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Language:English
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Summary: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. [Display omitted] •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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2021.07.026