Jeanny Kwon1, Dan Hyo Kim2, Ji Min Park2, Young Hee Park1, Yeo Hyun Hwang2, Hong-Gyun Wu3, Kyung Hwan Shin1, In Ah Kim4. 1. Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea. 2. Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 3. Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Institute of Radiation Medicine, Seoul National University, Seoul, Republic of Korea. 4. Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Institute of Radiation Medicine, Seoul National University, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea. Electronic address: inah228@snu.ac.kr.
Abstract
PURPOSE: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in human cancer cells. METHODS AND MATERIALS: U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed. RESULTS: Of the 4 PI4K isotypes, specific inhibition of IIIα increased radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by half-maximal inhibitory concentration assay. Simeprevir was selected, and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of phospho-phospho-PKC and phospho-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and down-regulation of phospho-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy. CONCLUSION: These data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiation therapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.
PURPOSE: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in humancancer cells. METHODS AND MATERIALS: U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed. RESULTS: Of the 4 PI4K isotypes, specific inhibition of IIIα increased radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by half-maximal inhibitory concentration assay. Simeprevir was selected, and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of phospho-phospho-PKC and phospho-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and down-regulation of phospho-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy. CONCLUSION: These data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiation therapy in various humancancers, such as glioma, breast, and hepatocellular carcinoma.
Authors: Walaa E Kattan; Junchen Liu; Dina Montufar-Solis; Hong Liang; Bhargavi Brahmendra Barathi; Ransome van der Hoeven; Yong Zhou; John F Hancock Journal: Proc Natl Acad Sci U S A Date: 2021-12-21 Impact factor: 12.779