1. Heterogeneous response of cancer-associated fibroblasts to the glucose deprivation through mitochondrial calcium uniporter.
- Author
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Hwang SH, Yang Y, Jung JH, and Kim Y
- Subjects
- Adenosine Triphosphate metabolism, Animals, Apoptosis, Biomarkers, Tumor genetics, Cancer-Associated Fibroblasts metabolism, Cell Cycle, Cell Movement, Cell Proliferation, Female, Fibroblasts metabolism, Fibroblasts pathology, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Mitochondria, Neoplasms metabolism, Prognosis, Survival Rate, Tumor Cells, Cultured, Tumor Microenvironment, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Calcium Channels metabolism, Cancer-Associated Fibroblasts pathology, Gene Expression Regulation, Neoplastic, Glucose deficiency, Neoplasms pathology
- Abstract
Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have distinct features from normal fibroblasts (NFs). However, the discriminative nature of heterogeneous CAFs under glucose starvation remains unknown. In this study, we investigated the changes in the mitochondrial calcium concentration and relevant intracellular machinery in CAFs under glucose-deficient conditions. Xenografted tumor masses were dissected into multiple pieces and subjected to the CAF isolation using magnetically activated cell sorting (MACS). NFs were separated from the normal lung and skin. Under glucose starvation, CAFs from the tumor mass exhibited heterogeneity in cell proliferation, ATP production and calcium concentration. Compared to NFs, mitochondrial calcium concentration was significantly higher in glucose-starved CAFs with upregulation of mitochondrial calcium uniporter (MCU) that led to enhancement of ATP production and cell growth. Intriguingly, treatment of glucose-starved CAFs with oligomycin increased apoptosis by disrupted calcium homeostasis following overactivation of the mPTP. Moreover, oligomycin-induced apoptosis was mitigated by calcium chelation. This study demonstrated that the discriminative calcium influx to mitochondria through MCU coordinated cell growth and apoptosis in glucose-starved CAFs but not in NFs., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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