title: T0070907, a PPAR γ inhibitor, induced G2/M arrest enhances the effect of radiation in human cervical cancer cells through mitotic catastrophe.
abstract: Overexpression of peroxisome proliferator activator receptor γ (PPARγ) has been implicated in many types of cancer including cervical cancer. Radiation therapy remains the main nonsurgical modality for the treatment of cervical cancer. The present study reports the impact of pharmacological inhibition of PPARγ in enhancing the radiosensitization of cervical cancer cells in vitro. Three cervical cancer cell lines (HeLa, SiHa, and Me180) were treated with a PPARγ inhibitor, T0070907, and/or radiation. The changes in protein, cell cycle, DNA content, apoptosis, and cell survival were analyzed. The PPARγ is differentially expressed in cervical cancer cells with maximum expression in ME180 cells. T0070907 has significantly decreased the tubulin levels in a time-dependent manner in ME180 cells. The decrease in the tubulin levels after T0070907 in ME180 and SiHa cells was associated with significant increase in the cells at the G2/M phase. The changes in the tubulin and G2/M phase were not evident in HeLa cells. T0070907 reduced the protein levels of PPARγ; however, PPARγ silencing had no effect on the α-tubulin level in ME180 cells suggesting the PPARγ-dependent and -independent actions of T0070907. To ascertain the impact of synergistic effect of T0070907 and radiation, HeLa and ME180 cells were pretreated with T0070907 and subjected to radiation (4 Gy). Annexin V-fluorescein isothiocyanate analysis revealed increased apoptosis in cells treated with radiation and T0070907 when compared to control and individual treatment. In addition, T0070907 pretreatment enhanced radiation-induced tetraploidization reinforcing the additive effect of T0070907. Confocal analysis of tubulin confirmed the onset of mitotic catastrophe in cells treated with T0070907 and radiation. These results strongly suggest the radiosensitizing effects of T0070907 through G2/M arrest and mitotic catastrophe.
authors.affiliation: Department of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.
authors.forename: Zhengzhe
authors.initials: Z
authors.lastname: An
authors.affiliation: Department of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Muthusami
authors.affiliation: Department of Environmental and Tropical Medicine, Konkuk University College of Medicine, Chungju, 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, Republic of Korea wynpark@chungbuk.ac.kr.
authors.forename: Woo-Yoon
authors.initials: WY
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001549:Benzamides / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000528:radiation effects*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects* / Q000528:radiation effects*; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D047495:PPAR gamma; D011725:Pyridines; D011838:Radiation-Sensitizing Agents; C458508:T 0070907; D014404:Tubulin
keywords: PPARγ; T0070907; cell cycle; cervical cancer; mitotic catastrophe; radiation