Potential Application of Leelamine as a Novel Regulator of Chemokine-Induced Epithelial-to-Mesenchymal Transition in Breast Cancer Cells

Abstract

CXCR7 and CXCR4 are G protein-coupled receptors (GPCRs) that can be stimulated by CXCL12 in various human cancers. CXCR7/4–CXCL12 binding can initiate activation of multiple pathways including JAK/STAT and manganese superoxide dismutase (MnSOD) signaling, and initiate epithelial–mesenchymal transition (EMT) process. It is established that cancer cell invasion and migration are caused because of these events. In particular, the EMT process is an important process that can determine the prognosis for cancer. Since the antitumor effect of leelamine (LEE) has been reported in various previous studies, here, we have evaluated the influence of LEE on the CXCR7/4 signaling axis and EMT processes. We first found that LEE suppressed expression of CXCR7 and CXCR4 both at the protein and mRNA levels, and showed inhibitory effects on these chemokines even after stimulation by CXCL12 ligand. In addition, LEE also reduced the level of MnSOD and inhibited the EMT process to attenuate the invasion and migration of breast cancer cells. In addition, phosphorylation of the JAK/STAT pathway, which acts down-stream of these chemokines, was also abrogated by LEE. It was also confirmed that LEE can induce an imbalance of GSH/GSSG and increases ROS, thereby resulting in antitumor activity. Thus, we establish that targeting CXCR7/4 in breast cancer cells can not only inhibit the invasion and migration of cancer cells but also can affect JAK/STAT, EMT process, and production of ROS. Overall, the findings suggest that LEE can function as a novel agent affecting the breast cancer.

Therapeutic Effects of Upadacitinib on Experimental Autoimmune Uveitis: Insights From Single-Cell Analysis

“…These genes have been associated with the JAK/STAT signaling pathway and implicated in the pathogenesis of various diseases. 24 , 25 Consistent with previous research, we identified several genes that could potentially serve as therapeutic targets for EAU, such as Pim1 , which could be inhibited to reduce the proportion of Th17 cells and increase the proportion of Tregs. 26 …”

Role of Culinary Indian Spices in the Regulation of TGF‐β Signaling Pathway in Inflammation‐Induced Liver Cancer

“…[43,44] It also regulates both intrinsic and extrinsic apoptosis by modulating different factors that include death associated kinase, death receptor fibroblast associated antigen, and B-cell lymphoma 2 family members. [45,46] TGF-𝛽 induces tumor progression by regulating processes like cell proliferation, metastasis, epithelial to mesenchymal transition (EMT). [47] TGF-𝛽 can inhibit the activity of tissue inhibitors by stimulating matrix metalloproteinases (MMP)-2 and MMP-9 thus stimulating tumor progression.…”

“…[ 49 ] TGF‐β has been found to induce EMT transition which enables the cancer cells to dissociate, penetrate the basal membrane, and undergo metastasis. [ 46 ] TGF‐β expression has been reported to be higher in highly invasive HCC, [ 50 ] and a dramatic increase in serum TGF‐β levels has also been reported in HCC patients. [ 51 ] On a transcriptional level, overexpression of a mutant SMAD‐2 protein can induce SMAD‐3/SMAD‐4 signaling which stimulates the transcriptional induction of VEGF, TGF‐β, and plasminogen activator inhibitor‐one (PAI‐1).…”

CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications

“…In contrast, the DRYLSIT motif was found in CXCR7, and this structural difference resulted in CXCR7's inability to signal through Gαi 40 . In addition, recent studies have also shown that CXCR7 activates intracellular signaling pathways, including protein kinase B (AKT) and JAK/STAT 41 , 42 .…”