Corosolic acid inhibits colorectal cancer cells growth as a novel HER2/HER3 heterodimerization inhibitor.

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Colorectal cancer (CRC) is the third most common cancer worldwide. HER2 and HER3 are two members of human epidermal receptor family of tyrosine kinase receptors (RTKs) and associated with poor survival in CRC. They have been observed as important therapeutic targets in various types of cancer. Corosolic acid (CRA), a natural pentacyclic triterpene has been demonstrated to have significant anticancer activity. However, the target of CRA has not yet been explored. This study aimed to reveal the direct targets of CRA underlying its anticancer activities.The targets of CRA were revealed by the phospho-RTK array, Bio-layer interferometry, co-immunoprecipitation and Proximity ligation assay. The inhibitory action of CRA on HER2/HER3 heterodimerization and related downstream signaling were investigated in HCT116 and SW480 cells. In addition, the chemopreventive effects of CRA were validated in both HCT116 xenograft model and AOM/DSS model.Our results demonstrated that CRA could prevent NRG1-induced HER2/HER3 heterodimerization and suppress the phosphorylation of both HER2 and HER3. Furthermore, HER2 and HER3 could regulate the downstream signaling pathways of RalA/RalBP1/CDK1 and PI3K/Akt/PKA respectively, resulting in the changes in phosphorylation of Drp1 and mitochondrial dynamics. CRA exhibited anticancer activity in both HCT116 xenograft model and AOM/DSS model.Collectively, our results demonstrated CRA directly targeted HER2 and HER3 heterodimerization and inhibited mitochondrial fission via regulating RalA/RalBP1/CDK1 and PI3K/Akt/PKA pathways, revealing a novel mechanism underlying the beneficial effects of CRA on CRC.

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