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

Abstract

VPS34-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.

• 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
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 214 Pg. 115634 (08 2023) ISSN: 1873-2968 [Electronic] England
• PMID: 37290596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• eIF-2 Kinase
• 1-((2-((2-chloropyridin-4yl)amino)-4'-(cyclopropylmethyl)-(4,5'-bipyrimidin)-2'-yl)amino)-2-methylpropan-2-ol
• Phosphatidylinositol 3-Kinases
• Activating Transcription Factor 4
• Transcription Factor CHOP

Topics

• eIF-2 Kinase (genetics, metabolism)
• Signal Transduction
• Phosphatidylinositol 3-Kinases (metabolism)
• Apoptosis
• Endoplasmic Reticulum Stress
• Activating Transcription Factor 4 (genetics, metabolism)
• Transcription Factor CHOP (genetics, metabolism)
• Neoplasms