PMID- 34314755
OWN - NLM
STAT- MEDLINE
DCOM- 20220105
LR  - 20220105
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 519
DP  - 2021 Oct 28
TI  - The NUPR1/p73 axis contributes to sorafenib resistance in hepatocellular 
      carcinoma.
PG  - 250-262
LID - S0304-3835(21)00353-0 [pii]
LID - 10.1016/j.canlet.2021.07.026 [doi]
AB  - 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.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Augello, Giuseppa
AU  - Augello G
AD  - Institute for Biomedical Research and Innovation, National Research Council, 
      Palermo, Italy.
FAU - Emma, Maria Rita
AU  - Emma MR
AD  - Institute for Biomedical Research and Innovation, National Research Council, 
      Palermo, Italy.
FAU - Azzolina, Antonina
AU  - Azzolina A
AD  - Institute for Biomedical Research and Innovation, National Research Council, 
      Palermo, Italy.
FAU - Puleio, Roberto
AU  - Puleio R
AD  - Istituto Zooprofilattico Sperimentale Della Sicilia "A. Mirri", Palermo, Italy.
FAU - Condorelli, Lucia
AU  - Condorelli L
AD  - Istituto Zooprofilattico Sperimentale Della Sicilia "A. Mirri", Palermo, Italy.
FAU - Cusimano, Antonella
AU  - Cusimano A
AD  - Institute for Biomedical Research and Innovation, National Research Council, 
      Palermo, Italy.
FAU - Giannitrapani, Lydia
AU  - Giannitrapani L
AD  - Institute for Biomedical Research and Innovation, National Research Council, 
      Palermo, Italy; Department of Health Promotion, Mother and Child Care, Internal 
      Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
FAU - McCubrey, James A
AU  - McCubrey JA
AD  - Department of Microbiology and Immunology, Brody School of Medicine at East 
      Carolina University, Greenville, NC, 27858, USA.
FAU - Iovanna, Juan Lucio
AU  - Iovanna JL
AD  - Centre de Recherche en Cancerologie de Marseille, INSERM U1068, CNRS UMR 7258, 
      Aix-Marseille Universite and Institut Paoli-Calmettes, Parc Scientifique et 
      Technologique de Luminy, Marseille, France.
FAU - Cervello, Melchiorre
AU  - Cervello M
AD  - Institute for Biomedical Research and Innovation, National Research Council, 
      Palermo, Italy. Electronic address: melchiorre.cervello@irib.cnr.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210724
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (NUPR1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (TP73 protein, human)
RN  - 0 (Tumor Protein p73)
RN  - 9ZOQ3TZI87 (Sorafenib)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics
MH  - Autophagy/genetics
MH  - Basic Helix-Loop-Helix Transcription Factors/*genetics
MH  - Carcinoma, Hepatocellular/*genetics/pathology
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Female
MH  - Hep G2 Cells
MH  - Humans
MH  - Liver Neoplasms/*genetics/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Proteins/*genetics
MH  - Sorafenib/pharmacology
MH  - Tumor Protein p73/*genetics
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - Hepatocellular carcinoma
OT  - NSC5994
OT  - NUPR1
OT  - p73
EDAT- 2021/07/28 06:00
MHDA- 2022/01/06 06:00
CRDT- 2021/07/27 20:14
PHST- 2021/03/26 00:00 [received]
PHST- 2021/06/24 00:00 [revised]
PHST- 2021/07/19 00:00 [accepted]
PHST- 2021/07/28 06:00 [pubmed]
PHST- 2022/01/06 06:00 [medline]
PHST- 2021/07/27 20:14 [entrez]
AID - S0304-3835(21)00353-0 [pii]
AID - 10.1016/j.canlet.2021.07.026 [doi]
PST - ppublish
SO  - Cancer Lett. 2021 Oct 28;519:250-262. doi: 10.1016/j.canlet.2021.07.026. Epub 
      2021 Jul 24.