Ginkgolide B Regulates CDDP Chemoresistance in Oral Cancer via the Platelet-Activating Factor Receptor Pathway
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Published on: January 18, 2017
Kohei Kawasaki1, Atsushi Kasamatsu2, Toshiaki Ando1
1Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi 260-8670, Japan.
Abstract:
The platelet-activating factor receptor (PAFR) is a key molecule that participates in intracellular signaling pathways, including regulating the activation of kinases. It is involved in cancer progression, but the detailed mechanism of its chemosensitivity is unknown. The purpose of the current study was to elucidate the mechanism regulating cisplatin (CDDP) sensitivity through PAFR functions in oral squamous cell carcinoma (OSCC). We first analyzed the correlation between PAFR expression and CDDP sensitivity in seven OSCC-derived cell lines based upon cell viability assays. Among them, we isolated 2 CDDP-resistant cell lines (Ca9-22 and Ho-1-N-1). In addition to conducting PAFR-knockdown (siPAFR) experiments, we found that ginkgolide B (GB), a specific inhibitor of PAFR, enhanced both CDDP chemosusceptibility and apoptosis. We next evaluated the downstream signaling pathway of PAFR in siPAFR-treated cells and GB-treated cells after CDDP treatment. In both cases, we observed decreased phosphorylation of ERK and Akt and increased expression of cleaved caspase-3. These results suggest that PAFR is a therapeutic target for modulating CDDP sensitivity in OSCC cells. Thus, GB may be a novel drug that could enhance combination chemotherapy with CDDP for OSCC patients.
Insights
Platelet-activating factor receptor (PAFR) inhibition enhances cisplatin sensitivity in oral cancer. Ginkgolide B, a PAFR inhibitor, boosts chemotherapy effectiveness by promoting apoptosis and reducing key signaling proteins.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Platelet-activating factor receptor (PAFR) plays a role in cancer progression, but its precise mechanism in chemosensitivity remains unclear.
- Understanding PAFR's function is crucial for developing targeted therapies in oral squamous cell carcinoma (OSCC).
Purpose of the Study:
- To investigate the role of PAFR in regulating cisplatin (CDDP) sensitivity in OSCC.
- To elucidate the downstream signaling pathways affected by PAFR inhibition in CDDP-treated OSCC cells.
Main Methods:
- Cell viability assays were used to assess CDDP sensitivity in OSCC cell lines with varying PAFR expression.
- PAFR was inhibited using knockdown (siPAFR) and a specific inhibitor, ginkgolide B (GB).
- Downstream signaling pathways (ERK, Akt, cleaved caspase-3) were analyzed following CDDP treatment in inhibited cells.
Main Results:
- Two CDDP-resistant OSCC cell lines (Ca9-22 and Ho-1-N-1) were identified.
- PAFR knockdown and GB treatment significantly enhanced CDDP chemosusceptibility and induced apoptosis.
- Inhibition of PAFR led to decreased phosphorylation of ERK and Akt, and increased cleaved caspase-3 expression.
Conclusions:
- PAFR acts as a therapeutic target for overcoming CDDP resistance in OSCC.
- Ginkgolide B shows potential as a novel agent to enhance combination chemotherapy with CDDP for OSCC patients.
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