Abstract
Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.
Highlights
Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment and the predominant reason for the poor survival and reduced quality of life of tumor patients [1]
G protein coupled estrogen receptor (GPER) activation inhibited the severity of CIM induced by 5-FU without affecting the antitumor effect of 5 -FU Increased inflammatory infiltration, abruption between the epithelial layer and lamina propria, shortening of villus length, and necrosis of crypt cells was observed in 5-FU-induced CIM model
Our study revealed that GPER activation reduced the intestinal histological damage, weight loss, and mucosal barrier dysfunction, protected crypt cell proliferation and inhibited apoptosis in a CIM model
Summary
Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment and the predominant reason for the poor survival and reduced quality of life of tumor patients [1]. Chemotherapeutic drugs targeting tumor cells elicit their antineoplastic effects by interfering with DNA replication to inhibit cell division, induce cell cycle arrest and apoptosis [6, 7]. Crypt cell damage associated with DNA damage, such as apoptosis and proliferation inhibition, is one of the key mechanisms of CIM [8, 12,13,14,15]. Enhancing the survival of crypt cells following chemotherapy should be a potential effective treatment for CIM
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