BACKGROUND This study is to investigate the effects of zoledronic acid (ZA) on TSC2-null cell proliferation and on the tumor progression and recurrence in mouse models of lymphangioleiomyomatosis (LAM). METHODS Subcutaneous mouse models and LAM mouse models were established. Immunohistochemistry and immunofluorescence were performed to detect the protein expression levels. TUNEL assay was conducted to detect cell apoptosis. Immunoprecipitation was carried out to determine the interaction between proteins. RESULTS ZA prevented the growth of TSC2-null cells both in culture and in LAM mouse models. Compared with rapamycin, ZA more effectively promoted the apoptosis of TSC2-null cells. Moreover, combined with the rapamycin, ZA effectively suppressed the tumor recurrence after drug withdrawal and ZA inhibited the activity of GTPase RhoA by decreasing protein geranylgeranylation, resulting in changes of Yap nucleus translocation. CONCLUSION ZA promotes cell apoptosis in TSC2-null cells through the RhoA/YAP signaling pathway. ZA may be used for the clinical treatment of LAM.

中文翻译：

---

在淋巴管平滑肌瘤病小鼠模型中，唑来膦酸通过 RhoA/YAP 信号通路抑制 TSC2-null 细胞肿瘤生长。

背景 本研究旨在探讨唑来膦酸 (ZA) 对 TSC2-null 细胞增殖以及淋巴管平滑肌瘤病 (LAM) 小鼠模型中肿瘤进展和复发的影响。方法建立皮下小鼠模型和LAM小鼠模型。进行免疫组织化学和免疫荧光以检测蛋白质表达水平。进行TUNEL法检测细胞凋亡。进行免疫沉淀以确定蛋白质之间的相互作用。结果 ZA 阻止了 TSC2 无效细胞在培养和 LAM 小鼠模型中的生长。与雷帕霉素相比，ZA更有效地促进了TSC2-null细胞的凋亡。此外，与雷帕霉素合用，ZA有效抑制停药后的肿瘤复发，ZA通过降低蛋白质香叶基香叶酰化抑制GTP酶RhoA的活性，导致Yap核易位的变化。结论 ZA通过RhoA/YAP信号通路促进TSC2缺失细胞凋亡。ZA可用于LAM的临床治疗。