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Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway
Chunming Jiang1, Shenglin Ma2, Runlei Hu3
1Department of Pediatrics, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.
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.
Insights
Down-regulating CXCR4 in osteosarcoma cells inhibits proliferation and promotes apoptosis via the PI3K/Akt/NF-κβ pathway. This suggests CXCR4 is a potential therapeutic target for osteosarcoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Osteosarcoma is a primary bone cancer with increasing global incidence.
- Apoptosis is crucial for osteosarcoma treatment efficacy.
- CXCR4 is implicated in tumor progression and metastasis.
Purpose of the Study:
- To investigate the role of CXCR4 in osteosarcoma cell proliferation and apoptosis.
- To elucidate the signaling pathways involved in CXCR4-mediated effects on osteosarcoma cells.
Main Methods:
- CXCR4 knockdown using shRNA.
- Cell proliferation measured by BrdU assay.
- Apoptosis assessed by flow cytometry and Western blot.
- Caspase activity and NF-κβ signaling analyzed.
- PI3K/Akt/NF-κβ pathway and endoplasmic reticulum stress (ERS) investigated.
Main Results:
- CXCR4 down-regulation reduced osteosarcoma cell proliferation and increased apoptosis.
- Apoptosis induction was caspase-dependent and involved PI3K/Akt/NF-κβ pathway inhibition.
- Endoplasmic reticulum stress activation was implicated in CXCR4-down-regulation-induced apoptosis.
Conclusions:
- Down-regulation of CXCR4 induces apoptosis in human osteosarcoma cells by inhibiting the PI3K/Akt/NF-κβ signaling pathway.
- CXCR4 represents a potential therapeutic target for osteosarcoma.
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