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Inhibition of PI4K III? radiosensitizes in human tumor xenograft and immune-competent syngeneic murine tumor model.

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 III? 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 III? 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 III? induced by simeprevir combined with radiation significantly delayed tumor growth compared to either treatment alone. PI4K III? inhibition led to eversion of the epithelial-mesenchymal transition as suggested by decreased invasion/migration and vascular tube formation. Simeprevir down-regulated PI3K? expression and PI3K? inhibition using RNA interference radiosensitized breast cancer cells. PI4K III? inhibition enhanced the radiosensitizing effect of anti-programmed death-ligand 1 (PD-L1) and decreased the expression of PI3K?, 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 III? 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 III? via modulation of PI3K? suggests a strategy for enhancing the radiosensitizing effect of immune checkpoint blockades.

SUBMITTER: Park Y

PROVIDER: S-EPMC5746391 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Inhibition of PI4K IIIα radiosensitizes in human tumor xenograft and immune-competent syngeneic murine tumor model.

Park Younghee Y Park Ji Min JM Kim Dan Hyo DH Kwon Jeanny J Kim In Ah IA

Oncotarget 20171130 66

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 <i>in vitro</i>. In this study, we investigated the radiosensitizing effect of simeprevir in an <i>in vivo</i> tumor xenograft model and the mechanism of its interaction. The immune modulatory effect of PI4K IIIα was evaluated in an immune-competent syn ...[more]

PMID: 29299156

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Inhibition of PI4K III? radiosensitizes in human tumor xenograft and immune-competent syngeneic murine tumor model.

Publications

Inhibition of PI4K IIIα radiosensitizes in human tumor xenograft and immune-competent syngeneic murine tumor model.

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