PMID- 32369692
OWN - NLM
STAT- MEDLINE
DCOM- 20201111
LR  - 20211204
IS  - 1421-9778 (Electronic)
IS  - 1015-8987 (Linking)
VI  - 54
IP  - 3
DP  - 2020 May 6
TI  - Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative 
      Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells.
PG  - 457-473
LID - 10.33594/000000230 [doi]
AB  - BACKGROUND/AIMS: Orthotopic liver transplantation (OLT) is the recommended 
      treatment for patients at early stages of hepatocarcinoma (HCC) with portal 
      hypertension and/or increased bilirubinemia, but without vascular-associated 
      diseases. Tumor recurrence, which is the main drawback for the survival of 
      patients submitted to OLT for HCC, has been related to tumor-related variables 
      and the immunosuppressive therapies. We have previously shown that Tacrolimus 
      (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than 
      the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in 
      liver cancer cells. This study identified the role of the immunosuppressant 
      partners such as FK506-binding proteins (FKBPs) in the induction of cell death 
      and arrest of cell proliferation by immunosuppressants in two representative 
      liver cancer cells. METHODS: The regulation of endoplasmic reticulum (ER) stress, 
      apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in 
      Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and 
      hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell 
      death and proliferation was also addressed using the siRNA technology. The 
      assessed antitumoral properties of the immunosuppressants were associated to 
      microRNAs (miRNAs) pattern. RESULTS: The enhanced pro-apoptotic and 
      anti-proliferative properties of Tacrolimus versus mTOR inhibitors were 
      associated with increased protein kinase RNA-like endoplasmic reticulum kinase 
      (PERK)-related ER stress, (Ser15)P-p53/p53 ratio and p21 protein expression that 
      may counterbalance the risk of proliferative upregulation caused by enhanced 
      (Thr172)P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR 
      pathway by Sirolimus and Everolimus was related to an induction of autophagy; and 
      at a high dose, these drugs impaired translation likely at a very early step of 
      the elongation phase. Tacrolimus and mTOR inhibitors increased the protein 
      expression of FKBP12 and FKBP51 that appeared to play pro-survival role. 
      Interestingly, the administration of immunosuppressants yields a specific pattern 
      of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, 
      miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, 
      miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. CONCLUSION: The 
      more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus 
      mTOR inhibitors were associated with an increased activation of PERK and p53 
      signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most 
      relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival 
      effect in HepG2 cells. The observed effects of immunosuppressants were related to 
      a specific miRNA signature in liver cancer cells.
CI  - (c) Copyright by the Author(s). Published by Cell Physiol Biochem Press.
FAU - Navarro-Villaran, Elena
AU  - Navarro-Villaran E
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
FAU - de la Cruz-Ojeda, Patricia
AU  - de la Cruz-Ojeda P
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
FAU - Contreras, Laura
AU  - Contreras L
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Department of Genetics, University of Seville, Seville, Spain.
FAU - Gonzalez, Raul
AU  - Gonzalez R
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
FAU - Negrete, Maria
AU  - Negrete M
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
FAU - Rodriguez-Hernandez, Maria A
AU  - Rodriguez-Hernandez MA
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
FAU - Marin-Gomez, Luis M
AU  - Marin-Gomez LM
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - Department of General Surgery, Hospital University "Virgen del Rocio"/CSIC/ 
      University of Seville/IBiS, Seville, Spain.
FAU - Alamo-Martinez, Jose M
AU  - Alamo-Martinez JM
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - Department of General Surgery, Hospital University "Virgen del Rocio"/CSIC/ 
      University of Seville/IBiS, Seville, Spain.
FAU - Calvo, Antonio
AU  - Calvo A
AD  - Department of General Surgery, Hospital University of Puerto Real, Puerto Real, 
      Spain.
FAU - Gomez-Bravo, Miguel A
AU  - Gomez-Bravo MA
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - Department of General Surgery, Hospital University "Virgen del Rocio"/CSIC/ 
      University of Seville/IBiS, Seville, Spain.
FAU - de la Cruz, Jesus
AU  - de la Cruz J
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Department of Genetics, University of Seville, Seville, Spain.
FAU - Padillo, Javier
AU  - Padillo J
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - Department of General Surgery, Hospital University "Virgen del Rocio"/CSIC/ 
      University of Seville/IBiS, Seville, Spain.
FAU - Muntane, Jordi
AU  - Muntane J
AD  - Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del 
      Rocio"/CSIC/University of Seville, Seville, Spain, jmuntane-ibis@us.es.
AD  - Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD o 
      Ciberehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - Department of General Surgery, Hospital University "Virgen del Rocio"/CSIC/ 
      University of Seville/IBiS, Seville, Spain.
LA  - eng
GR  - PI13/00021, P16/00090, PI19/01266/Institute of Health Carlos III (ISCiii) 
      cofinanced by the European Regional Development Fund "A way to achieve Europe" 
      (ERDF)/
GR  - Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd), 
      Institute of Health Carlos III (ISCiii) cofinanced by the European Regional 
      Development Fund "A way to achieve Europe" (ERDF)/
GR  - IFI18/00014/Institute of Health Carlos III (ISCiii)/
GR  - CTS-6264/Andalusian Ministry of the Economy, Innovation, Science and Employment/
GR  - PI13/00025, PI16/0198, PIP-0215-2020, PI-0216-2020/Andalusian Ministry of Health/
GR  - FPU17/00026, FPU16/05127/Spanish Ministry of Education (MEC)/
GR  - BFU2016-75352-P AEI/FEDER, EU/Spanish Ministry of Economy and Competitiveness 
      (MINECO) cofinanced by the European Regional Development Fund "A way to achieve 
      Europe" (ERDF)/
PT  - Journal Article
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (EIF2AK3 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - EC 5.2.1.- (Tacrolimus Binding Proteins)
RN  - EC 5.2.1.8 (tacrolimus binding protein 5)
RN  - W36ZG6FT64 (Sirolimus)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Autophagy/drug effects
MH  - Carcinoma, Hepatocellular/genetics/*metabolism/pathology
MH  - Cell Proliferation/drug effects
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - Endoplasmic Reticulum Stress/drug effects
MH  - Everolimus/pharmacology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Hep G2 Cells
MH  - Hepatocytes/drug effects
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Liver Neoplasms/genetics/*metabolism/pathology
MH  - MicroRNAs/genetics/metabolism
MH  - RNA, Small Interfering
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Tacrolimus/*pharmacology
MH  - Tacrolimus Binding Protein 1A/metabolism
MH  - Tacrolimus Binding Proteins/*metabolism
MH  - Tumor Suppressor Protein p53/metabolism
MH  - eIF-2 Kinase/metabolism
OTO - NOTNLM
OT  - Apoptosis; Autophagy; Endoplasmic reticulum stress; Immunosuppressants; 
      Hepatocarcinoma
COIS- The authors have no conflicts of interest to declare.
EDAT- 2020/05/06 06:00
MHDA- 2020/11/12 06:00
CRDT- 2020/05/06 06:00
PHST- 2020/03/29 00:00 [accepted]
PHST- 2020/05/06 06:00 [entrez]
PHST- 2020/05/06 06:00 [pubmed]
PHST- 2020/11/12 06:00 [medline]
AID - 10.33594/000000230 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2020 May 6;54(3):457-473. doi: 10.33594/000000230.