VPS34-IN1 induces apoptosis of ER  + breast cancer cells via activating PERK/ATF4/CHOP pathway

Biochem Pharmacol. 2023 Jun 6:115634. doi: 10.1016/j.bcp.2023.115634. Online ahead of print.ABSTRACTVPS34-IN1 is a specific selective inhibitor of Class III Phosphatidylinositol 3-kinase (PI3K) and has been shown to exhibit a significant antitumor effect in leukemia and liver cancer. In current study, we focused on the anticancer effect and potential mechanism of VPS34-IN1 in estrogen receptor positive (ER + ) breast cancer. Our results revealed that VPS34-IN1 inhibited the viability of ER + breast cancer cells in vitro and in vivo. Flow cytometry and western blot analyses showed that VPS34-IN1 treatment induced breast cancer cell apopotosis. Interestingly, VPS34-IN1 treatment activated protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. Furthermore, knockdown of PERK by siRNA or inhibition of PERK activity by chemical inhibitor GSK2656157 could attenuate VPS34-IN1-mediated apoptosis in ER + breast cancer cells. Collectively, VPS34-IN1 has an antitumor effect in breast cancer, and it may result from activating PERK/ATF4/CHOP pathway of ER stress to induce cell apoptosis. These findings broaden our understanding of the anti-breast cancer effects and mechanisms of VPS34-IN1 and provide new ideas and reference directions for the treatment of ER + breast cancer.PMID:37290596 | DOI:10.1016/j.bcp.2023.115634

Source: Biochemical Pharmacology - June 8, 2023 Category: Drugs & Pharmacology Authors: Qiuya Wu Duanfang Zhou Zhengze Shen Bo Chen Gang Wang Lihong Wu Limei Zhang Xiaoli Li Lie Yuan Yuanli Wu Na Qu Weiying Zhou Source Type: research