Differential influence of tacrolimus and sirolimus on mitochondrial-dependent signaling for apoptosis in pancreatic cells

Andrei Alexandru Constantinescu; Malak Abbas; Mohamad Kassem; Céline Gleizes; Guillaume Kreutter; Valerie Schini-Kerth; Ioan Liviu Mitrea; Florence Toti; Laurence Kessler

doi:10.1007/s11010-016-2736-8

Article dans une revue

Differential influence of tacrolimus and sirolimus on mitochondrial-dependent signaling for apoptosis in pancreatic cells

Andrei Alexandru Constantinescu ^{1, 2, 3, 4} Malak Abbas ^{5, 1} Mohamad Kassem ¹ Céline Gleizes ¹ Guillaume Kreutter ¹ Valerie Schini-Kerth ⁶ Ioan Liviu Mitrea ² Florence Toti ⁶ Laurence Kessler ^{1, 7}

1 Stress vasculaire et tissulaire en transplantation : microparticules et environnement

2 University of Agronomic Science and Veterinary Medicine-Bucharest

3 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer

4 LNC - Lipides - Nutrition - Cancer (U866)

5 Université Libanaise, Ecole Doctorale des Sciences et de Technologie

6 LBP - Laboratoire de Biophotonique et Pharmacologie - UMR 7213

7 Service de Médecine Interne - Diabète et Maladies métaboliques (CHU de Strasbourg)

Abstract : To examine and compare the mitochondria-related cellular mechanisms by which tacrolimus (TAC) or sirolimus (SIR) immunosuppressive drugs alter the pancreatic exocrine and endocrine beta-cell fate. Human exocrine PANC-1 and rat endocrine insulin-secreting RIN-m5F cells and isolated rat islets were submitted to 1-100 nM TAC or SIR. In cultures, insulin secretion was measured as endocrine cell function marker. Apoptosis was quantified by annexin 5 and propidium iodide staining. Cleaved caspase-3, Bax apoptosis indicators, and p53, p21 cell cycle regulators were detected by Western blot. Cell cycle and mitochondrial membrane potential (Delta Im) were analyzed by flow cytometry and SA-beta-galactosidase (SA-beta-gal) activity by fluorescence microscopy. Only TAC reduced insulin secretion by RIN-m5F after 24 h. TAC and SIR promoted moderate apoptosis in both PANC-1 and RIN-m5F after 24 h. Apoptosis was associated with up-regulated Bax (threefold) and cleaved caspase-3 (fivefold) but only in PANC-1, while p53 and p21 were up-regulated (twofold) in both cell lines. Delta Im was impaired only in PANC-1 by TAC and SIR. Only SIR prompted cell cycle arrest in both cell lines. The induction of a premature senescence-like phenotype was confirmed in isolated islets by SA-beta-gal activity. TAC and SIR are early inducers of pancreatic cell dysfunction and apoptosis but differentially alter endocrine and exocrine cells via mitochondrial-driven pathways. In rat islets, TAC and SIR prompt a senescence-like phenotype.

Keywords : Diabetes-Mellitus Sirolimus Mitochondria-related apoptosis Cellular premature senescence Endocrine beta-cells Exocrine cells Tacrolimus Functional-Changes Insulin-Secretion Mammalian Target Rapamycin Mtor Beta-Cells Kappa-B Islets Transplantation Langerhans

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Biologie cellulaire

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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01430997
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Soumis le : mardi 10 janvier 2017 - 14:48:39
Dernière modification le : lundi 6 décembre 2021 - 10:46:18

Differential influence of tacrolimus and sirolimus on mitochondrial-dependent signaling for apoptosis in pancreatic cells

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