In vitro , in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma

Oncotarget
Stéphanie DayotThierry Voisin

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant in vitro and ex vivo. We analyzed in vivo the hypocretin-1/orexin-A and almorexant effect on tumor growth in mice xenografted with PDAC cell lines expressing, or not, OX1R. Ninety-six percent of PDAC expressed OX1R, while adjacent normal exocrine pancreas did not. OX1R was expressed in pre-cancerous lesions. In vitro, under hypocretin-1/orexin-A and almorexant, the OX1R-positive AsPC-1 cells underwent apoptosis, abolished by the tyrosine phosphatase SHP2 inhibitor, NSC-87877, whereas the OX1R-negative HPAF-II cell line did not. These effects were mediated by phosphorylation of OX1R and recruitment of SHP2. Ex vivo, caspase-3 positive tumor cells were significantly higher in fresh tumour slices treated 48h with hypocretin-1/orexin-A, as compared to control, whereas cellul...Continue Reading

References

Jun 14, 2000·Current Opinion in Neurobiology·P Tsao, M von Zastrow
Feb 13, 2001·Trends in Pharmacological Sciences·P TsaoM von Zastrow
Mar 5, 2003·Cellular and Molecular Life Sciences : CMLS·T VoisinM Laburthe
Aug 20, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Marie-Pierre BraletCatherine Guettier
Sep 9, 2005·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·G GarceaD P Berry
Jan 11, 2008·Annual Review of Pharmacology and Toxicology·Aylin C Hanyaloglu, Mark von Zastrow
Jan 17, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Thierry VoisinMarc Laburthe
Feb 26, 2008·Acta Physiologica·M V HeinonenK H Herzig
Mar 18, 2008·Journal of Pharmacological Sciences·Kousaku OhnoTakeshi Sakurai
Jul 24, 2008·International Journal of Cancer. Journal International Du Cancer·Susanne Sebens MüerkösterHeiner Schäfer
Jul 26, 2008·Molecular Cancer·Rainer HamacherGünter Schneider
Oct 18, 2008·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Jean Claude Reubi, Helmut R Maecke
Aug 8, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Aadil El FirarMarc Laburthe
Sep 2, 2009·Acta Physiologica·M LaburtheA El Firar
Jan 5, 2011·Nature Reviews. Drug Discovery·Rosamaria Lappano, Marcello Maggiolini
Apr 7, 2011·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Carlo CapellaUNKNOWN Società Italiana di Anatomia Patologica e Citopatologia Diagnostica/International Academy of Pathology, Italian division (SI
Jun 2, 2012·Frontiers in Oncology·Juan IovannaJean-Charles Dagorn
Feb 11, 2014·Current Opinion in Cell Biology·Morgan O'HayreJ Silvio Gutkind
Nov 27, 2014·The New England Journal of Medicine·David P RyanNabeel Bardeesy
Aug 25, 2015·Pharmacology & Therapeutics·Cindy NeuzilletPascal Hammel
Jan 9, 2016·CA: a Cancer Journal for Clinicians·Rebecca L SiegelAhmedin Jemal
Oct 19, 2016·Molecular Pharmacology·Claudio M Costa-NetoMichel Bouvier

❮ Previous
Next ❯

Citations

Nov 7, 2019·Frontiers in Endocrinology·Alain CouvineauYossan-Var Tan
Apr 3, 2019·Marine Drugs·Sara García-DavisNancy Elena Guzmán-Delgado
Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Couvineau AlainVoisin Thierry

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
FCS
immunoprecipitation
xenografting
Assay
pancreatectomy
xenografts
xenograft

Software Mentioned

GraphPad Prism

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

© 2022 Meta ULC. All rights reserved