Blockage of progesterone receptor effectively protects pancreatic islet beta cell viability

Abstract

The progesterone receptor (PR), a member of nuclear receptor superfamily, is closely associated with gestational, type 1 and type 2 diabetes. However, the underlying mechanisms remain obscure. Here we found that PR activation increased the pro-inflammatory cytokines (PIC)-induced injury in Min6 cells, and PR blockage with siRNA interference protected the cells from damage. Moreover, the new discovered PR antagonist SC51089 effectively improved cell survival by reducing the PIC-stimulated cell apoptosis in Min6 cells. Immunoblotting assays indicated that either PR agonist progesterone (P4) or PR-B over-expression promoted the PIC-induced reinforces of extracellular-signal-regulated kinase 1/2 phosphorylation (p-Erk) and protein 53 (p53), and the attenuations of protein kinase B phosphorylation (p-AKT) and tumor necrosis factor receptor-associated factor 2 (TRAF2). SC51089 could reverse all the P4- or PR-B over-expression induced effects. In addition, PR siRNA inference based assay further supported that SC51089 protected pancreatic islet beta cells from the PR activation or PIC-induced injury by targeting PR and this protective action was mediated by AKT signaling pathway. To our knowledge, this current work might be the first report on the regulation of PR in pancreatic islet beta cell survival. It is expected that SC51089, as a non-steroid PR antagonist, might also find its potential in anti-diabetic research.

Keywords: 9-cis retinoic acid; AKT; AR; Cort; DHT; DMEM; DMSO; Dex; Diabetes; ERα; Erk; Est; Estrone; FBS; GR; GW; GW501516; IFNγ; IL-1β; LXRα; MAPK; MR; Mif; NR; P4; PIC; PPARδ/γ; PR; PR elements; PR knockout; PR-KO; PRE; Pancreatic islet beta cells; Pro-inflammatory cytokines; Progesterone receptor; RA; RXRα; Rosi; SC51089; TNFα; TO; TO901317; TRAF2; androgen receptor; corticosterone; dexamethasone; dihydro-testosterone; dimethyl sulfoxide; dulbecco’s modified eagle’s medium; estrogen receptor α; extracellular-signal-regulated kinase 1/2; fetal bovine serum; glucocorticoid receptor; interferon-γ; interleukin-1β; liver X receptorα; mifepristone; mineralocorticoid receptor; mitogen-activated protein kinases; nuclear receptor; p53; peroxisome proliferator-activated receptorδ/γ; pro-inflammatory cytokines; progesterone; progesterone receptor; protein 53; protein kinase B; retinoid X receptor α; rosiglitazone; tumor necrosis factor receptor-associated factor 2; tumor necrosis factor α.