Reactivating Hippo by Drug Compounds to Suppress Gastric Cancer and Enhance Chemotherapy Sensitivity

Zhifa Cao; Yu Hou; Zhangting Zhao; Hui Zhang; Luyang Tian; Yiming Zhang; Chao Dong; Fenghua Guo; Lijie Tan; Yi Han; Wenjia Wang; Shi Jiao; Yang Tang; Liwei An; Zhaocai Zhou

doi:10.1016/j.jbc.2024.107311

Reactivating Hippo by Drug Compounds to Suppress Gastric Cancer and Enhance Chemotherapy Sensitivity

J Biol Chem. 2024 Apr 22:107311. doi: 10.1016/j.jbc.2024.107311. Online ahead of print.

Authors

Zhifa Cao¹, Yu Hou², Zhangting Zhao³, Hui Zhang², Luyang Tian², Yiming Zhang³, Chao Dong⁴, Fenghua Guo⁵, Lijie Tan⁶, Yi Han³, Wenjia Wang², Shi Jiao², Yang Tang⁷, Liwei An⁸, Zhaocai Zhou⁹

Affiliations

¹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China; Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China.
² State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
³ Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China.
⁴ Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650000, China.
⁵ Department of General Surgery, Hua'shan Hospital, Fudan University Shanghai Medical College, Shanghai, 200040, China.
⁶ Department of Thoracic Surgery, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
⁷ Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: tangyang@tongji.edu.cn.
⁸ Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: lwan@tongji.edu.cn.
⁹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China; Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: zhouzhaocai@fudan.edu.cn.

PMID: 38657866
DOI: 10.1016/j.jbc.2024.107311

Abstract

The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e. Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa-STRN3-MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulfiram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme, and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via a MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identified thiram (TH), a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and TH on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa-STRN3-MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment.

Keywords: Chemotherapy; Drug compound; Gastric cancer; Hippo signaling; STRIPAK.