Dataset Information

A CD10-OGP Membrane Peptolytic Signaling Axis in Fibroblasts Regulates Lipid Metabolism of Cancer Stem Cells via SCD1.

ABSTRACT: Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral peptide termed osteogenic growth peptide (OGP). OGP restrains the expression of rate-limiting desaturase SCD1 and inhibits lipid desaturation, which is required for cancer stem cells (CSCs). Targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10-OGP signals are associated with the response to neoadjuvant chemotherapy in patients with breast cancer. The collective data suggest that a nexus between the niche and lipid metabolism in CSCs is a promising therapeutic target for breast cancer.

SUBMITTER: Yu S

PROVIDER: S-EPMC8498877 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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A CD10-OGP Membrane Peptolytic Signaling Axis in Fibroblasts Regulates Lipid Metabolism of Cancer Stem Cells via SCD1.

Yu Shubin S Lu Yiwen Y Su An A Chen Jianing J Li Jiang J Zhou Boxuan B Liu Xinwei X Xia Qidong Q Li Yihong Y Li Jiaqian J Huang Min M Ye Yingying Y Zhao Qiyi Q Jiang Sushi S Yan Xiaoqing X Wang Xiaojuan X Di Can C Pan Jiayao J Su Shicheng S

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210807 19

Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral p ...[more]

PMID: 34363355

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Project description:The incidence of Poorly cohesive carcinoma (PCC) has steadily risen in recent years, posing a significant clinical challenge. To reveal the anti-tumor effects of Jianpi Yangzheng Xiaozheng granule (JPYZXZ) in PCC, an initial investigation was performed using CCK-8, colony formation, scratch, and transwell assays. This was followed by network pharmacology studies to gain a deeper understanding of JPYZXZ's impact on gastric cancer (GC). Then reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA), glutathione (GSH), Oil Red O staining, BODIPY493/503, triglyceride (TG), and cholesterol (TC) assay kits and western blot (Wb) analysis were applied to exam the regulatory effects of JPYZXZ on ferroptosis and lipid metabolism. Additionally, molecular docking studies and Wb analysis were used to further investigate the mechanisms of JPYZXZ on PCC. Finally, in vivo animal studies were conducted. The results show that JPYZXZ can inhibit the proliferation and migration of PCC cell. It increases the levels of ROS, Fe2+, MDA, while declining the content of GSH, TC, TG, and lipid droplet accumulation within cellular compartments. Wb indicates that JPYZXZ can negatively regulate the expression of proteins, including glutathione peroxidase 4 (GPX4), cystine/glutamate antipoter SLC7A11 (xCT), fatty acid synthase (FASN), and acetyl coenzyme A carboxylase 1 (ACC1). Furthermore, ferrostatin-1 (fer-1) is able to reverse the effects of JPYZXZ on the aforementioned markers of ferroptosis and lipid metabolism. Molecular docking analyses reveal that JPYZXZ exhibits a favorable binding affinity towards Stearoyl-Coenzyme A desaturase 1 (SCD1). Mechanism studies demonstrate that JPYZXZ is capable of down-regulating the expressions of proteins like SCD1, β-catenin, GPX4, and xCT, which is analogous to the effects of SCD1 knockdown and the application of SCD1 inhibitor A939572. Nevertheless, when SCD1 is knocked down, JPYZXZ is unable to further downregulate the expressions of these proteins. Animal studies have corroborated the in vitro tumor-inhibiting effects of JPYZXZ. Therefore, this study offers the first evidence that JPYZXZ inhibits PCC progression by orchestrating ferroptosis and altering lipid metabolism, mediated by the SCD1/Wnt/β-catenin pathway.

Dataset Information

A CD10-OGP Membrane Peptolytic Signaling Axis in Fibroblasts Regulates Lipid Metabolism of Cancer Stem Cells via SCD1.

Publications

A CD10-OGP Membrane Peptolytic Signaling Axis in Fibroblasts Regulates Lipid Metabolism of Cancer Stem Cells via SCD1.

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