Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
Gene. 2021 Feb 15;769:145243. doi: 10.1016/j.gene.2020.145243. Epub 2020 Oct 16.
Deficiency of folliculin (FLCN) may lead to renal cell carcinoma (RCC) in patients with Birt-Hogg-Dubé (BHD) disease. In this study, we investigated the cytotoxicity induced by PARP inhibitor olaparib in FLCN deficient RCC cells, and the interaction between FLCN and BRCA1 A complex-regulated DNA repair pathway.
FLCN expressing (ACHN and UOK257-F) and FLCN deficient (ACHN-2 and UOK257) cell lines were used in this research. Cell viability was detected by clonogenic assay and MTT assay. Flow cytometry and TUNEL assay were used to detect apoptosis. Autophagy in cells was measured by MDC assay, western blot, and transmission electron microscopy. Co-immunoprecipitation, immunofluorescence and western blot experiments were performed to determine the interaction between FLCN protein and BRCA1 A complex. The in vivo experiments were performed in a xenograft model by inoculating UOK 257 in nude mice.
RCC cells with FLCN protein deficiency were more sensitive to olaparib treatment than the cells with FLCN expression. Olaparib treatment led to more severe autophagy and apoptosis in FLCN deficient ACHN-2 and UOK257 cells compared to the FLCN expressing ACHN and UOK257-F cells. Decreased BRCA1 A complex expression and disruption of DNA repair ability were detected in FLCN-deficient cells, suggesting that FLCN deficiency impaired BRCA1 A complex expression and sensitized cells to PARP inhibitor olaparib.
RCC cells deficient in FLCN are sensitive to olaparib treatment due to the impairment of BRCA1 A complex associated DNA repair ability. The results suggest that PARP inhibitor, such as olaparib, may be a potentially effective therapeutic approach for kidney tumors with deficiency of FLCN protein.
成纤维细胞生长因子受体（FGFR）信号通路的异常激活与多种肿瘤的发生、发展密切相关。在本研究中，我们检测了 FGFR 抑制剂 erdafitinib 在 FGFR 突变的膀胱癌中的抗肿瘤作用，并探讨了其作用机制。
我们使用了表达 FGFR3 融合基因的膀胱癌 T24 细胞株和 FGFR 野生型的 5637 细胞株进行实验。细胞增殖实验检测细胞活力，克隆形成实验检测细胞增殖能力，流式细胞术检测细胞凋亡，Western blot 检测凋亡相关蛋白的表达，免疫荧光检测 FGFR3 蛋白的表达和磷酸化水平。
FGFR 抑制剂 erdafitinib 能够显著抑制 FGFR3 融合基因阳性的 T24 细胞的增殖，并诱导其凋亡。进一步的机制研究表明，erdafitinib 能够抑制 FGFR3 蛋白的表达和磷酸化水平，从而阻断 FGFR 信号通路的激活。
FGFR 抑制剂 erdafitinib 能够抑制 FGFR3 融合基因阳性的膀胱癌 T24 细胞的增殖并诱导其凋亡，提示 FGFR 抑制剂可能成为治疗 FGFR 突变的膀胱癌的一种潜在治疗方法。
