CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to limited targeted therapies and poor patient outcomes.
• The eukaryotic translation initiation factor 2 alpha (eIF2α)/protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway is implicated in cancer progression and survival.

Purpose of the Study:

• To investigate the anti-tumor effects of CCT020312, a selective eIF2α/PERK activator, on triple-negative breast cancer (TNBC).
• To elucidate the molecular mechanisms underlying CCT020312's action in TNBC models.

Main Methods:

• In vitro studies utilized TNBC cell lines (MDA-MB-453, CAL-148) to assess cell viability, apoptosis, and cell cycle progression.
• Western blot analysis was performed to evaluate protein expression levels of key cell cycle regulators and apoptosis markers.
• In vivo efficacy was assessed using an MDA-MB-453 orthotopic xenograft mouse model.

Main Results:

• CCT020312 significantly inhibited TNBC cell viability by inducing apoptosis and G1 phase cell cycle arrest.
• Treatment with CCT020312 modulated the expression of proteins involved in cell cycle regulation (CDK4, CDK6, cyclin D1) and apoptosis (Bcl-2, Bax, cleaved PARP).
• CCT020312 activated the PERK/eIF2α/ATF4/CHOP signaling pathway while simultaneously inhibiting the AKT/mTOR pathway, both in vitro and in vivo, leading to reduced tumor growth.

Conclusions:

• CCT020312 demonstrates potent anti-tumor activity against TNBC through the modulation of key signaling pathways.
• The findings suggest that CCT020312 holds potential as a novel therapeutic agent for the treatment of triple-negative breast cancer.