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

by Selleckchem | Oct 14 2023

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.

Comments:

The study you mentioned focuses on the anticancer effects of VPS34-IN1, a selective inhibitor of Class III Phosphatidylinositol 3-kinase (PI3K), in estrogen receptor positive (ER+) breast cancer. The researchers found that VPS34-IN1 inhibited the viability of ER+ breast cancer cells both in vitro and in vivo. They also observed that treatment with VPS34-IN1 induced apoptosis (programmed cell death) in breast cancer cells, as evidenced by flow cytometry and western blot analyses.

An interesting finding of the study is that VPS34-IN1 treatment activated the protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. ER stress is a cellular response to various stimuli, including nutrient deprivation and accumulation of misfolded proteins in the ER. The activation of the PERK branch of ER stress is known to promote apoptosis. In this study, the researchers demonstrated that VPS34-IN1-induced apoptosis in ER+ breast cancer cells was associated with the activation of the PERK/ATF4/CHOP pathway, which is a signaling cascade involved in ER stress-mediated cell death.

To further investigate the role of PERK in VPS34-IN1-mediated apoptosis, the researchers performed experiments using siRNA to knock down PERK expression or a chemical inhibitor called GSK2656157 to inhibit PERK activity. They found that both approaches attenuated the apoptosis induced by VPS34-IN1 treatment in ER+ breast cancer cells. These results suggest that the activation of the PERK/ATF4/CHOP pathway plays a critical role in the antitumor effect of VPS34-IN1 in breast cancer.

Overall, this study expands our understanding of the mechanisms underlying the anticancer effects of VPS34-IN1 and provides potential directions for the treatment of ER+ breast cancer. By activating the PERK/ATF4/CHOP pathway of ER stress, VPS34-IN1 induces apoptosis in ER+ breast cancer cells, highlighting its potential as a therapeutic agent for this subtype of breast cancer.