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FBXL5 depletion as a novel strategy against osteosarcoma: Evidence for MEK/ERK inhibition and enhanced therapeutic
Yan-Chao Ma1, Wen-Ming Zhou1,2, Yong-Qiang Shi1,2
1Department of Orthopedics, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
Abstract:
Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents. Despite standard treatments, including surgery and chemotherapy, the 5-year survival rate for metastatic OS remains <20%, underscoring the need for novel therapeutic targets. F-box and leucine-rich repeat protein 5 (FBXL5) is an E3 ubiquitin ligase that regulates iron homeostasis and exhibits complex functions across different tumors; however, its role in OS is still unclear. The present study employed the MG63 and 143B OS cell lines to investigate the oncogenic potential of FBXL5 through in vitro and in vivo experiments. Lentivirus-mediated FBXL5 knockdown significantly suppressed cell proliferation, migration and invasion, while promoting apoptosis. RNA sequencing analysis after FBXL5 silencing revealed significant alterations in the mitogen-activated protein kinase signaling pathway, particularly affecting the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) axis. Consequently, FBXL5 depletion reduced the expression and phosphorylation of Ras, Raf, MEK and ERK. In a mouse xenograft tumor model, FBXL5 knockdown inhibited tumor growth and reduced tumor volume. These findings suggest that FBXL5 promotes OS progression via regulation of the MEK/ERK signaling pathway, suggesting that it may be a useful therapeutic target and potential prognostic indicator; further validation in larger clinical cohorts is warranted.
Insights
F-box and leucine-rich repeat protein 5 (FBXL5) promotes osteosarcoma progression by regulating the MEK/ERK pathway. Targeting FBXL5 may offer a new therapeutic strategy for this bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma (OS) is a primary bone cancer with poor survival rates for metastatic cases.
- Novel therapeutic targets are crucial for improving OS treatment outcomes.
- The role of F-box and leucine-rich repeat protein 5 (FBXL5), an E3 ubiquitin ligase, in OS remains unexplored.
Purpose of the Study:
- To investigate the oncogenic potential of FBXL5 in osteosarcoma.
- To elucidate the molecular mechanisms underlying FBXL5's function in OS.
- To evaluate FBXL5 as a potential therapeutic target for osteosarcoma.
Main Methods:
- Utilized MG63 and 143B OS cell lines for in vitro experiments.
- Performed lentivirus-mediated FBXL5 knockdown to assess its functional impact.
- Conducted RNA sequencing to analyze signaling pathway alterations post-FBXL5 silencing.
- Evaluated FBXL5's effect on tumor growth in a mouse xenograft model.
Main Results:
- FBXL5 knockdown significantly inhibited OS cell proliferation, migration, and invasion.
- Silencing FBXL5 promoted apoptosis in OS cells.
- FBXL5 depletion altered the mitogen-activated protein kinase (MAPK) signaling pathway, specifically the MEK/ERK axis.
- FBXL5 knockdown reduced tumor growth and volume in vivo.
Conclusions:
- FBXL5 acts as an oncogene in osteosarcoma progression.
- FBXL5 promotes OS by regulating the MEK/ERK signaling pathway.
- FBXL5 represents a potential therapeutic target and prognostic indicator for osteosarcoma, warranting further clinical investigation.
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