title: Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1.
abstract: Zoledronic acid (ZOL), a third-generation bisphosphonate that strongly inhibits osteoclast activity, is widely used for the treatment of bone metastasis from a variety of malignancies, including renal cell carcinoma (RCC). We previously reported that zoledronic acid (ZOL) clinically potentiates antitumor effects of radiotherapy (RT) on bone metastases from RCC. To date, however, it remains unknown whether ZOL radiosensitizes RCC and if it does, how. Here, we demonstrated that ZOL directly radiosensitizes RCC cells independent of osteoclast activity by potentiating the caspase-3-mediated apoptosis pathway. The radiosensitization by ZOL was observed in 786-O, A-498, and ACHN cells but not in Caki-1 cells. As its underlying molecular mechanism, we found that the signal transducer and activator of transcription 1 (STAT1) plays a key role. The three RCC cell lines, in which ZOL exerted a radiosensitizing effect, expressed STAT1 abundantly but Caki-1 cells did not. ZOL downregulated endogenous STAT1 expression in 786-O, A-498, and ACHN cells by a post-transcriptional modification. We confirmed that knockdown of endogenous STAT1 by siRNA sensitized 786-O cells to RT equivalently to ZOL, and that introduction of exogenous STAT1 rendered Caki-1 cells more RT-resistant. This is the first study to clarify the molecular mechanism by which ZOL directly radiosensitizes tumor cells. Because tumor cells commonly overexpress STAT1 and ZOL reportedly radiosensitizes various types of tumor cells, ZOL warrants further clinical and translational studies as a potent radiosensitizer against RT-resistant tumors overexpressing STAT1.
authors.affiliation: Graduate School of the Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kijima
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Koga
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujii
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yoshida
authors.forename: Manabu
authors.initials: M
authors.lastname: Tatokoro
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kihara
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D009928:Organ Specificity; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000077211:Zoledronic Acid; D053148:Caspase 3