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

Author:

Lyu Xiao-Dan1,Liu Yang12ORCID,Wang Jia1,Wei Yuan-Cheng1,Han Yi1,Li Xue1,Zhang Qian1,Liu Zheng-Rui1,Li Zheng-Zheng1,Jiang Jing-Wei3,Hu Hao-Lin4,Yuan Sheng-Tao5,Sun Li1

Affiliation:

1. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China

2. School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China

3. Shuangyun BioMed Sci & Tech Co., Ltd., Suzhou 215000, China

4. General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China

5. Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China

Abstract

Background: The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown. Methods: Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip. Results: C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte–breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures. Conclusion: C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2.

Funder

National Natural Science Foundation of China

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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