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Chemokine CCL20 promotes the paclitaxel resistance of CD44⁺CD117⁺ cells via the Notch1 signaling pathway in ovarian cancer.

ABSTRACT: Studies have found that C‑C motif chemokine ligand 20 (CCL20)/C‑C motif chemokine receptor 6 (CCR6)/notch receptor 1 (Notch1) signaling serves an important role in various diseases, but its role and mechanism in ovarian cancer remains to be elucidated. The aim of the present study was to investigate the underlying mechanism of CCL20/CCR6/Notch1 signaling in paclitaxel (PTX) resistance of a CD44⁺CD117⁺ subgroup of cells in ovarian cancer. The CD44⁺CD117⁺ cells were isolated from SKOV3 cells, followed by determination of the PTX resistance and the CCR6/Notch1 axis. Notch1 was silenced in the CD44⁺CD117⁺ subgroup and these cells were treated with CCL20, followed by examination of PTX resistance and the CCR6/Notch1 axis. Furthermore, in nude mice, CD44⁺CD117⁺ and CD44^‑CD117^‑ cells were used to establish the xenograft model and cells were treated with PTX and/or CCL20, followed by proliferation, apoptosis, reactive oxygen species (ROS) and mechanism analyses. Higher expression levels of Oct4, CCR6, Notch1 and ATP binding cassette subfamily G member 1 (ABCG1), increased sphere formation ability, IC₅₀ and proliferative ability, as well as lower ROS levels and apoptosis were observed in CD44⁺CD117⁺ cells compared with the CD44^‑CD117^‑ cells. It was found that CCL20 could significantly increase the expression levels of Oct4, CCR6, Notch1 and ABCG1, enhance the IC₅₀, sphere formation ability and proliferation, as well as decrease the ROS and apoptosis levels in the CD44⁺CD117⁺ cells. However, Notch1 knockdown could markedly reverse these changes. Moreover, CCL20 could significantly increase the proliferation and expression levels of Oct4, CCR6, Notch1 and ABCG1 in the CD44⁺CD117⁺ groups compared with the CD44^‑CD117^‑ groups. After treatment with PTX, apoptosis and ROS levels were decreased in the CD44⁺CD117⁺ groups compared with the CD44^‑CD117^‑ groups. Collectively, the present results demonstrated that, via the Notch1 pathway, CCL20/CCR6 may promote the stemness and PTX resistance of CD44⁺CD117⁺ cells in ovarian cancer.

SUBMITTER: Chen M

PROVIDER: S-EPMC8280726 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid. Metronomic dosing, the frequent administration of chemotherapeutics at substantially lower than maximum tolerated doses (MTD), has been shown to result in reduced normal tissue toxicity and to minimize "off-treatment" exposure resulting in an improved therapeutic ratio.We tested the hypothesis that hyaluronic acid (HA) conjugates of paclitaxel (TXL; HA-TXL) would exert strong antitumor effects with metronomic (MET) dosing and induce antiangiogenic effects superior to those achieved with MTD administration or with free TXL. Female nude mice bearing SKOV3ip1 or HeyA8 ovarian cancer cells were treated intraperitoneally (i.p.) with MET HA-TXL regimens (or MTD administration) to determine therapeutic and biologic effects.All MET HA-TXL-treated mice and the MTD group revealed significantly reduced tumor weights and nodules compared with controls (all P values < 0.05) in the chemotherapy-sensitive models. However, the MTD HA-TXL-treated mice showed significant weight loss compared with control mice, whereas body weights were not affected in the metronomic groups in HeyA8-MDR model, reflecting reduced toxicity. In the taxane-resistant HeyA8-MDR model, significant reduction in tumor weight and nodule counts was noted in the metronomic groups whereas the response of the MTD group did not achieve significance. While both MTD and metronomic regimens reduced proliferation (Ki-67) and increased apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), only metronomic treatment resulted in significant reductions in angiogenesis (CD31, microvessel density). Moreover, metronomic treatment resulted in substantial increases in thrombospondin-1 (Tsp-1), an inhibitor of angiogenesis.This study showed that MET HA-TXL regimens have substantial antitumor activity in ovarian carcinoma, likely via a predominant antiangiogenic mechanism.

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Chemokine CCL20 promotes the paclitaxel resistance of CD44⁺CD117⁺ cells via the Notch1 signaling pathway in ovarian cancer.

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Chemokine CCL20 promotes the paclitaxel resistance of CD44⁺CD117⁺ cells via the Notch1 signaling pathway in ovarian cancer.