Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway

Abstract

Background/Aims: Osteosarcoma, the most common primary bone malignancy, arises from primitive transformed cells of mesenchymal origin with the worldwide increasing morbidity and mortality. Previous studies found apoptosis of osteosarcoma cells was essential for an effective manner to improve the progress of osteosarcoma, and CXCR4 has been demonstrated to be relevant with various tumor progress and metastasis. Methods: The proliferation of cells transfected with CXCR4 shRNA and control shRNA were measured by BrdU assay. Apoptosis was detected by flow cytometry. Apoptotic protein expression levels were detected by Western blot. Caspase activity was detected by Colorimetric Assay Kits using microplate reader. Activation of NF-κβ signaling after CXCR4 down-regulation in osteosarcoma cells was examined by constructing NF-κβ promoter luciferase reporter plasmid. The expression and activation of NF-κβ Signaling relevant protein were analyzed to investigate the relationship between Akt and NF-κβ signaling after the down-regulation of CXCR4 in osteosarcoma cells. Results: Down-regulation of CXCR4 significantly reduced the cell proliferation, while remarkably increased the cell apoptosis and apoptotic protein expression levels in osteosarcoma cells. Furthermore, down-regulation of CXCR4 induced cell apoptosis was caspase dependent in osteosarcoma cells. This study also showed CXCR4 down-regulation induced apoptosis through inhibiting PI3K/Akt/NF-κβ signaling pathway. In addition, endoplasmic reticulum stress (ERS) activation was involved in cell apoptosis induced down-regulation of CXCR4. Knockdown of partial ERS relevant proteins followed down-regulation of CXCR4 significantly inhibited cell apoptosis and the apoptotic protein expression levels. Conclusions: Taken together, the results demonstrated that down-regulation of CXCR4 could induce apoptosis of human osteosarcoma cells through inhibiting PI3K/Akt/NF-κβ signaling pathway, indicating that CXCR4 could be vital for the clinical therapy of osteosarcoma.

Inhibition of ITGB1 enhance the anti-tumor effect of cetuximab in colorectal cancer cell

“…[ 33 ] Previous study also found that CXCL12/CXCR4 is critical for cell proliferation via activation of ERK signaling pathway, [ 34 ] and there is also study indicated that down-regulation of CXCR4 reduce the proliferation of cancer cells via inhibition of NF-κB signaling pathway with induction of cellular apoptosis. [ 35 ] Thus, we speculated that cetuximab targeted on Ras/Raf/MAPK signaling pathway, leading to the reduction in signaling pathway activation. Besides, we found that inhibition of ITGB1 targets on CXCL12/CXCR4, the upstream molecular of Ras/Raf/MAPK signaling pathway, resulting in reduction of cellular proliferation.…”

FtH-Mediated ROS Dysregulation Promotes CXCL12/CXCR4 Axis Activation and EMT-Like Trans-Differentiation in Erythroleukemia K562 Cells

“…In K562 shFtH cells, CXCR4 up-regulation promotes the nuclear translocation of p65 subunit belonging to the transcriptional complex NF-κB. There is increasing evidence suggesting a reciprocal interplay between CXCR4 and NF-κB signaling in fine tuning cancer cellular signaling pathways (23,24). Although the vast majority of data report that NF-κB contributes to the increase in CXCR4 expression (64), few recent reports suggest the possible existence of a regulatory feedback loop (24).…”

“…In chronic myelogenous leukemia (CML) cells, CXCR4 activates PI3K/AKT signaling pathway and promotes the translocation of NF-κB complexes into nucleus thereby decreasing the expression of pro-apoptotic proteins (23,24). Moreover, CXCL12 activates pro-survival signal pathways including those mediated by MAPK, S-6-kinase, STAT3 and STAT5, and in vitro treatment with CXCR4 antagonists inhibits cell growth and induces cell death (25,26).…”

High Expression of CXCR4, Instead of PD-L1, Is Correlated with Poor Clinical Response to R-CHOP Therapy in Diffuse Large B-cell Lymphoma Patients

“…8 Interaction of CXCR4 and CXCL12 activates intracellular signals, such as JAK2/STAT3, MEK/ERK and PI3K/AKT pathway to promote cell proliferation, migration, and survival. Jiang et al 23 reported that CXCR4 downregulation induces osteosarcoma cells apoptosis through inhibition of PI3K/AKT/NF-kB pathway. PI3K/AKT pathway is an intracellular signaling pathway which involves in DLBCL lymphomagenesis.…”