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 -CD117cells 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, IC 50 and proliferative ability, as well as lower ROS levels and apoptosis were observed in CD44 + CD117 + cells compared with the CD44 -CD117cells. It was found that CCL20 could significantly increase the expression levels of Oct4, CCR6, Notch1 and ABCG1, enhance the IC 50 , 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 -CD117groups. After treatment with PTX, apoptosis and ROS levels were decreased in the CD44 + CD117 + groups compared with the CD44 -CD117groups. 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.

Gastric cancer biomarker analysis in patients treated with different adjuvant chemotherapy regimens within SAMIT, a phase III randomized controlled trial

“…CD44 protein is overexpressed on the cell surface of cancer stem cells in GC tissues, and binding of hyaluronan to CD44 has been reported to affect various downstream signaling pathways, leading to cancer invasion, metastasis, and resistance to chemoradiotherapy 36 – 42 . As for paclitaxel resistance, ovarian cancer has been reported to exhibit higher levels of CD44 expression than paclitaxel-sensitive cancer cells 43 .…”

Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

“…The Notch1 signaling pathway mediates paclitaxel (PTX) resistance in CD44 + CD117 + OC cells promoted by chemokine CCL20. 247 The activated Notch3 pathway mediates the nuclear receptor NR2F6 to promote epithelial OC (EOC) cells’ resistance to cisplatin. 248 Similarly, Notch3 enhances EMT in OC cells and attenuates carboplatin-induced apoptosis.…”

Defining the Role of Metastasis-Initiating Cells in Promoting Carcinogenesis in Ovarian Cancer

“…Furthermore, the higher expression level of CD117 in extracellular vesicles from OC cells is positively correlated to more aggressive tumor invasion [89]. Given that CD44 also serves as an initiation-associated factor, the combination of CD117 and CD44 has been applied to identify cell subpopulations with relatively higher stemness potential [90][91][92].…”