Reactivating Hippo by drug compounds to suppress gastric cancer and enhance chemotherapy sensitivity

• DOI: 10.1016/j.jbc.2024.107311
• Publication Date: 2024-04-22T15:46:47Z
• Authors: 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
• Keywords: Hippo signaling pathway

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