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The GLP-1R Agonist Exendin-4 Attenuates Hyperglycemia-Induced Chemoresistance in Human Endometrial Cancer Cells Through ROS-Mediated Mitochondrial Pathway.

ABSTRACT: This study aimed to assess the effects of the antidiabetic drug Exendin-4 (Exe-4), a GLP-1 receptor agonist, on the response of human endometrial cancer cells to chemotherapy under high glucose (HG) conditions. Cell viability was detected using a cell counting kit (CCK)-8. Cell apoptosis and reactive oxygen species (ROS) levels were measured by flow cytometry. Gene expression was evaluated by real-time PCR and immunoblotting. The chemotherapeutic drug cisplatin (DDP) dose-dependently inhibited both human endometrial adenocarcinoma Ishikawa and HEC1B cells, a response reversed by HG. Meanwhile, Exe-4 attenuated hyperglycemia's effect by elevating intracellular lactate dehydrogenase (LDH) and ROS production. Similarly, DDP-induced elevation of intracellular rhodamine123 was attenuated by HG, and Exe-4 reversed HG's impact. The chemoresistance genes multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (Pgp) were upregulated. At the same time, topoisomerase II (TOPO II) was downregulated under HG conditions, suggesting HG-induced chemoresistance. Exe-4 did not significantly influence the above genes. DDP downregulated Bcl-2 and Bcl-XL and upregulated Bax, cytosolic cytochrome c, and PARP under normal glucose (NG) versus HG conditions, and Exe-4 attenuated these effects. Upstream of Bax/Bcl, acetylated P53 was upregulated by DDP and downregulated by HG, whose effect was reversed by Exe-4. DPP treatment significantly induced apoptosis and cell cycle arrest in the S phase under NG, and HG reduced these effects. Prolonged exposure to HG induces DDP chemoresistance in human endometrial cancer cells but is alleviated by Exe-4.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8721044 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic ? cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.

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The GLP-1R Agonist Exendin-4 Attenuates Hyperglycemia-Induced Chemoresistance in Human Endometrial Cancer Cells Through ROS-Mediated Mitochondrial Pathway.

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