Abstract
Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na+/Ca2+/Li+ exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa2+ overload, mitochondrial depolarization, decreased expression of cell-cycle genes and reduced tumor size in xenograft and spontaneous colorectal cancer mouse models. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, and expression of epithelial-to-mesenchymal, hypoxia, and stem cell pathways. Mechanistically, mtCa2+ overload leads to increased mitochondrial reactive oxygen species, which activate HIF1α signaling supporting metastasis of NCLX-null tumor cells. Thus, loss of NCLX is a novel driver of metastasis, indicating that regulation of mtCa2+ is a novel therapeutic approach in metastatic colorectal cancer.
Highlights
Mitochondria are adaptable cellular organelles critical for a spectrum of essential functions including ATP generation, cell signaling, metabolism, proliferation, and death (Vyas et al, 2016)
We demonstrate that a loss of Na+/Ca2+/ Li+ exchanger (NCLX) decreases mtCa2+ extrusion in Colorectal cancer (CRC) cells and that this increase in mtCa2+ has important consequences on colorectal tumor cells: NCLX loss (1) inhibits proliferation and primary tumor growth, while (2) enhances metastasis, and drug resistance, suggesting that a loss of NCLX contributes to CRC metastatic progression
Using the publicly available Cancer Genome Atlas (TCGA) database, we found that NCLX (SLC8B1) mRNA levels were significantly downregulated in both colon and rectal adenocarcinoma (COADREAD) tumors as compared to the adjacent normal tissue (Figure 1A)
Summary
Mitochondria are adaptable cellular organelles critical for a spectrum of essential functions including ATP generation, cell signaling, metabolism, proliferation, and death (Vyas et al, 2016). This central function causes mitochondria to fulfill a crucial role as mediators of tumorigenesis. Mitochondria sense changes in energetic, biosynthesis, and cellular stress, and adapt to the surrounding tumor environment to modulate cancer progression and drug resistance Even in cases where the cancer is diagnosed and treated early, cells can sometimes survive treatment and spread to other organs. Once the cancer has spread, the survival rate is less than 15%
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