Zoledronic acid inhibits TSC2-null cell tumor growth via RhoA/YAP signaling pathway in mouse models of lymphangioleiomyomatosis

Dandan Zhao; Jing Wu; Yinjuan Zhao; Wei Shao; Qi Cheng; Xiaoyan Shao; Xianwen Yuan; Juan Ye; Jianpu Gao; Meiling Jin; Chaojun Li; Xiaolin Chen; Yue Zhao; Bin Xue

doi:10.1186/s12935-020-1131-4

Zoledronic acid inhibits TSC2-null cell tumor growth via RhoA/YAP signaling pathway in mouse models of lymphangioleiomyomatosis

Cancer Cell Int. 2020 Feb 10:20:46. doi: 10.1186/s12935-020-1131-4. eCollection 2020.

Authors

Dandan Zhao^#¹, Jing Wu^#², Yinjuan Zhao³, Wei Shao², Qi Cheng¹, Xiaoyan Shao¹, Xianwen Yuan^{1

4}, Juan Ye^{1

5}, Jianpu Gao², Meiling Jin⁶, Chaojun Li^{1

7}, Xiaolin Chen⁸, Yue Zhao^{1

7}, Bin Xue^{2

1

7

9}

Affiliations

¹ 2State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine and School of Medicine, Nanjing University, Nanjing, 210093 Jiangsu China.
² 1Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166 Jiangsu China.
³ 3Collaborative Innovation Center of Sustainable Forestry in Southern China, College of Forestry, Nanjing Forestry University, Nanjing, 210037 Jiangsu China.
⁴ 4Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008 Jiangsu China.
⁵ 5Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028 Jiangsu China.
⁶ 6Pulmonary Department, Zhongshan Hospital, Fudan University, Shanghai, 200032 China.
⁷ 7Jiangsu Key Laboratory of Molecular Medicine and School of Medicine, Nanjing University, Nanjing, 210093 Jiangsu China.
⁸ 9Respiratory Department, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166 Jiangsu China.
⁹ 8State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009 Jiangsu China.

^# Contributed equally.

Abstract

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.

Keywords: Autophagy; Lymphangioleiomyomatosis; MTOR; YAP; Zoledronic acid (ZA).