Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic and multi-functional type I cell surface membrane protein, which is known to be phosphorylated by the activated platelet-derived growth factor receptor (PDGFR). The tyrosine kinase inhibitor imatinib, which inhibits PDGFR and c-Abl, and which has previously been reported to counteract β-cell death and diabetes, has been suggested to reduce atherosclerosis by inhibiting PDGFR-induced LRP1 phosphorylation. The aim of the present study was to study LRP1 function in β-cells and to what extent imatinib modulates LRP1 activity. LRP1 and c-Abl gene knockdown was performed by RNAi using rat INS-1 832/13 and human EndoC1-βH1 cells. LRP1 was also antagonized by treatment with the antagonist low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1). We have used PDGF-BB, a PDGFR agonist, and apolipoprotein E (ApoE), an LRP1 agonist, to stimulate the activities of PDGFR and LRP1 respectively. Knockdown or inhibition of LRP1 resulted in increased hydrogen peroxide (H2O2)- or cytokine-induced cell death, and glucose-induced insulin release was lowered in LRP1-silenced cells. These results indicate that LRP1 function is necessary for β-cell function and that LRP1 is adversely affected by challenges to β-cell health. PDGF-BB, or the combination of PDGF-BB+ApoE, induced phosphorylation of extracellular-signal-regulated kinase (ERK), Akt and LRP1. LRP1 silencing blocked this event. Imatinib blocked phosphorylation of LRP1 by PDGFR activation but induced phosphorylation of ERK. LRP1 silencing blocked imatinib-induced phosphorylation of ERK. Sunitinib also blocked LRP1 phosphorylation in response to PDGF-BB and induced phosphorylation of ERK, but this latter event was not affected by LRP1 knockdown. siRNA-mediated knockdown of the imatinib target c-Abl resulted in an increased ERK phosphorylation at basal conditions, with no further increase in response to imatinib. Imatinib-induced cell survival of tunicamycin-treated cells was partially mediated by ERK activation. We have concluded that imatinib promotes LRP1-dependent ERK activation, possibly via inhibition of c-Abl, and that this could contribute to the pro-survival effects of imatinib on β-cells.

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

“…Rat and mouse beta cells are highly sensitive to palmitate treatment that induces dysfunction and apoptosis [3]. On the other hand, previous data indicated that treatment of EndoC-βH1 cells with palmitate does not induce lipotoxicity under standard culture conditions [51,52]. Our current data further confirm this.…”

c-Abl contributes to glucose-promoted apoptosis via p53 signaling pathway in podocytes

“…It also has a correlation with aggressive tumors [10] and plays an important role in inflammatory diseases [11]. In addition, many studies point toward the role of c-Abl in the signal transduction pathways that are invovled in apoptotic signaling and cytoskeletal rearrangement [12][13][14][15]. As a tumor suppressor, p53 plays a key role in many biological processes.…”

Novel members of quinoline compound family enhance insulin secretion in RIN-5AH beta cells and in rat pancreatic islet microtissue

“…glibenclamide) involve ERK1/2 phosphorylation that may also correlate with an increased insulin secretion28293031. The activation of ERK1/2 protein can be further beneficial to beta cells by promoting cell survival, which was described in a recent study with imatinib32. Time dependent treatments were performed with compound 9 in RIN-5AH cells and results were analyzed by western blot.…”