Abstract
Phosphatidylinositol (PI) 4-kinase (PI4K) has emerged as a potential target for anti-cancer treatment. We recently reported that simeprevir, an anti-hepatitis C viral (HCV) agent, radiosensitized diverse human cancer cells by inhibiting PI4K IIIα in vitro. In this study, we investigated the radiosensitizing effect of simeprevir in an in vivo tumor xenograft model and the mechanism of its interaction. The immune modulatory effect of PI4K IIIα was evaluated in an immune-competent syngeneic murine tumor model.In in vivo xenograft models using BT474 breast cancer and U251 brain tumor cells, inhibition of PI4K IIIα induced by simeprevir combined with radiation significantly delayed tumor growth compared to either treatment alone. PI4K IIIα inhibition led to eversion of the epithelial-mesenchymal transition as suggested by decreased invasion/migration and vascular tube formation. Simeprevir down-regulated PI3Kδ expression and PI3Kδ inhibition using RNA interference radiosensitized breast cancer cells. PI4K IIIα inhibition enhanced the radiosensitizing effect of anti-programmed death-ligand 1 (PD-L1) and decreased the expression of PI3Kδ, phosphorylated-Akt, and PD-L1 in breast cancer cells co-cultured with human T-lymphocytes. The immune modulatory effect in vivo was evaluated in immune-competent syngeneic 4T1 murine tumor models. Simeprevir showed significant radiosensitizing effect and immune modulatory function by affecting the CD4(+)/CD8(+) ratio of tumor infiltrating lymphocytes.These findings suggest that targeting PI4K IIIα with an anti-HCV agent is a viable drug repositioning approach for enhancing the therapeutic efficacy of radiation therapy. The immune regulatory function of PI4K IIIα via modulation of PI3Kδ suggests a strategy for enhancing the radiosensitizing effect of immune checkpoint blockades.
Highlights
Phosphatidylinositol 4-phosphate (PI4P), produced by PI 4-kinase (PI4K), is a common substrate for both the phospholipase C (PLC)/protein kinase C (PKC) pathways and PI 3-kinase (PI3K)/Akt pathways responsible for diverse cell functions and pathogenesis [1]
We recently reported that simeprevir, an anti-hepatitis C viral (HCV) agent, radiosensitized diverse human cancer cells by inhibiting PI4K IIIα in vitro
In our recent study [6], the radiosensitizing effect of simeprevir was demonstrated in various human cancer cell lines
Summary
Phosphatidylinositol 4-phosphate (PI4P), produced by PI 4-kinase (PI4K), is a common substrate for both the phospholipase C (PLC)/protein kinase C (PKC) pathways and PI 3-kinase (PI3K)/Akt pathways responsible for diverse cell functions and pathogenesis [1]. Inhibition of PI4K IIIα by simeprevir resulted in down-regulation of p-PKC and p-AKT, suggesting that simeprevir is an effective anti-cancer agent that simultaneously inhibits two important pathways known to be involved in both tumorigenesis and treatment resistance. Simeprevir prolonged γH2AX foci and down-regulated phospho-DNA-PKcs after irradiation, suggesting that the radiosensitizing effects were mediated through impaired nonhomologous end-joining repair. These results suggested the successful drug repositioning of simeprevir as a new anti-cancer agent. Based on these results, we investigated the radiosensitizing effect of PI4K IIIα inhibition in in vivo tumor models and evaluated the mechanisms of radiosensitization in this study
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