Cargando…

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

SIMPLE SUMMARY: ASCT2 is an attractive tumour metabolism target based on its critical role in cancer cell growth. The potential mechanisms of microtubule protein inhibitor C118P in breast cancer remain unknown. Identification of the potential target of C118P is essential. We evaluated the inhibitory...

Descripción completa

Detalles Bibliográficos
Autores principales: Lyu, Xiao-Dan, Liu, Yang, Wang, Jia, Wei, Yuan-Cheng, Han, Yi, Li, Xue, Zhang, Qian, Liu, Zheng-Rui, Li, Zheng-Zheng, Jiang, Jing-Wei, Hu, Hao-Lin, Yuan, Sheng-Tao, Sun, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605716/
https://www.ncbi.nlm.nih.gov/pubmed/37894450
http://dx.doi.org/10.3390/cancers15205082
_version_ 1785127144885583872
author Lyu, Xiao-Dan
Liu, Yang
Wang, Jia
Wei, Yuan-Cheng
Han, Yi
Li, Xue
Zhang, Qian
Liu, Zheng-Rui
Li, Zheng-Zheng
Jiang, Jing-Wei
Hu, Hao-Lin
Yuan, Sheng-Tao
Sun, Li
author_facet Lyu, Xiao-Dan
Liu, Yang
Wang, Jia
Wei, Yuan-Cheng
Han, Yi
Li, Xue
Zhang, Qian
Liu, Zheng-Rui
Li, Zheng-Zheng
Jiang, Jing-Wei
Hu, Hao-Lin
Yuan, Sheng-Tao
Sun, Li
author_sort Lyu, Xiao-Dan
collection PubMed
description SIMPLE SUMMARY: ASCT2 is an attractive tumour metabolism target based on its critical role in cancer cell growth. The potential mechanisms of microtubule protein inhibitor C118P in breast cancer remain unknown. Identification of the potential target of C118P is essential. We evaluated the inhibitory effects of C118P on breast cancer. C118P restrained the tumour growth of MDA-MB-231 cells by inducing apoptosis, G2/M phase arrest, and autophagy. Furthermore, ASCT2 was confirmed to be a target of C118P. This is the first report to provide evidence that ASCT2 might be a candidate target of C118P in breast cancer treatment. Remarkably, this study will provide an opportunity for ASCT2 inhibition as a therapeutic strategy. 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.
format Online
Article
Text
id pubmed-10605716
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-106057162023-10-28 A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer Lyu, Xiao-Dan Liu, Yang Wang, Jia Wei, Yuan-Cheng Han, Yi Li, Xue Zhang, Qian Liu, Zheng-Rui Li, Zheng-Zheng Jiang, Jing-Wei Hu, Hao-Lin Yuan, Sheng-Tao Sun, Li Cancers (Basel) Article SIMPLE SUMMARY: ASCT2 is an attractive tumour metabolism target based on its critical role in cancer cell growth. The potential mechanisms of microtubule protein inhibitor C118P in breast cancer remain unknown. Identification of the potential target of C118P is essential. We evaluated the inhibitory effects of C118P on breast cancer. C118P restrained the tumour growth of MDA-MB-231 cells by inducing apoptosis, G2/M phase arrest, and autophagy. Furthermore, ASCT2 was confirmed to be a target of C118P. This is the first report to provide evidence that ASCT2 might be a candidate target of C118P in breast cancer treatment. Remarkably, this study will provide an opportunity for ASCT2 inhibition as a therapeutic strategy. 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. MDPI 2023-10-20 /pmc/articles/PMC10605716/ /pubmed/37894450 http://dx.doi.org/10.3390/cancers15205082 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lyu, Xiao-Dan
Liu, Yang
Wang, Jia
Wei, Yuan-Cheng
Han, Yi
Li, Xue
Zhang, Qian
Liu, Zheng-Rui
Li, Zheng-Zheng
Jiang, Jing-Wei
Hu, Hao-Lin
Yuan, Sheng-Tao
Sun, Li
A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer
title A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer
title_full A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer
title_fullStr A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer
title_full_unstemmed A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer
title_short A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer
title_sort novel asct2 inhibitor, c118p, blocks glutamine transport and exhibits antitumour efficacy in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605716/
https://www.ncbi.nlm.nih.gov/pubmed/37894450
http://dx.doi.org/10.3390/cancers15205082
work_keys_str_mv AT lyuxiaodan anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT liuyang anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT wangjia anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT weiyuancheng anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT hanyi anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT lixue anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT zhangqian anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT liuzhengrui anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT lizhengzheng anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT jiangjingwei anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT huhaolin anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT yuanshengtao anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT sunli anovelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT lyuxiaodan novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT liuyang novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT wangjia novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT weiyuancheng novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT hanyi novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT lixue novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT zhangqian novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT liuzhengrui novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT lizhengzheng novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT jiangjingwei novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT huhaolin novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT yuanshengtao novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer
AT sunli novelasct2inhibitorc118pblocksglutaminetransportandexhibitsantitumourefficacyinbreastcancer