A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The microtubule inhibitor C118P demonstrates significant anti-breast cancer activity.
• The specific molecular targets and mechanisms underlying C118P's efficacy are not fully understood.

Purpose of the Study:

• To identify the molecular targets of C118P in breast cancer.
• To elucidate the mechanisms by which C118P exerts its anti-cancer effects.
• To investigate the role of the tumor microenvironment in C118P's action.

Main Methods:

• Real-time cellular analysis (RTCA) for cell viability.
• Flow cytometry for apoptosis and cell cycle analysis.
• Computational docking, Surface Plasmon Resonance (SPR), and MicroScale Thermophoresis (MST) to validate C118P-ASCT2 interaction.
• Seahorse XF technology for oxygen consumption rate (OCR) measurement.
• Co-culture models and cytokine arrays to assess the adipose microenvironment's influence.

Main Results:

• C118P inhibited breast cancer cell proliferation, induced apoptosis, and caused G2/M cell cycle arrest.
• Alanine-serine-cysteine transporter 2 (ASCT2) was confirmed as a direct target of C118P.
• C118P suppressed glutamine metabolism and mediated autophagy through ASCT2.
• Adipose-derived IL-6 promotes breast cancer proliferation via ASCT2; C118P counteracted this effect.

Conclusions:

• C118P exhibits anti-tumor effects in breast cancer by targeting the glutamine transporter ASCT2.
• C118P modulates glutamine metabolism and autophagy, impacting the tumor microenvironment.