title: T0070907 inhibits repair of radiation-induced DNA damage by targeting RAD51.
abstract: T0070907 (T007), a PPARγ inhibitor, can reduce α and β tubulin proteins in some cancer cell lines. Thus, T007 has been suggested as an antimicrotubule drug. We previously reported that T007 increased radiosensitivity by inducing mitotic catastrophe in cervical cancer cells. In this study, we investigated the underlying mechanisms of the T007-mediated increase in radiosensitivity. T007 pre-treatment attenuated RAD51 protein levels and ionising radiation (IR)-induced nuclear foci formation, resulting in more frequent centrosome amplification and multipolar mitotic spindle formation in cervical cancer cells. Furthermore, T007 pre-treatment delayed the clearance of IR-induced γ-H2AX and increased radiosensitivity in cervical cancer cells. In contrast, none of these changes were observed in normal cells. Our data demonstrate for the first time that T007 impairs the repair of IR-induced DNA double-strand breaks by inhibiting RAD51, a key protein in homologous recombination repair, increases IR-induced mitotic catastrophe, and leads to increased death of IR-treated cells. These findings support T007 as a potential RAD51 inhibitor to increase tumour response to radiation therapy.
authors.affiliation: Department of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea.
authors.forename: Zhengzhe
authors.initials: Z
authors.lastname: An
authors.affiliation: Department of Environmental and Tropical Medicine, Konkuk University College of Medicine, Chungju 27478, Republic of Korea.
authors.forename: Jae-Ran
authors.initials: JR
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea. Electronic address: wynpark@chungbuk.ac.kr.
authors.forename: Woo-Yoon
authors.initials: WY
authors.lastname: Park
mesh_terms: D001549:Benzamides / Q000633:toxicity*; D045744:Cell Line, Tumor; D004249:DNA Damage; D005720:Gamma Rays; D057809:HEK293 Cells; D006801:Humans; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000633:toxicity*; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001549:Benzamides; D047495:PPAR gamma; D011725:Pyridines; C458508:T 0070907; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: DNA double-strand breaks; Homologous recombination; Ionising radiation; RAD51; T0070907; γ-H2AX