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Abstract
Mutations leading to constitutive activation of the Wnt pathway and its target genes are frequently observed in cancer. The Wnt pathway promotes cell proliferation and increasing evidence supports its role also in cancer cell metabolism. This study aims to elucidate the role of the Wnt/β-catenin target gene CCND1 in these processes in colorectal cancer. We analyzed whether knock-down of CCND1 affects cell cycle progression and energy metabolism in a colorectal cancer cell line. Down-regulation of CCND1 led to retardation of the cell cycle. The proportion of cells in the G0 phase increased, while the amount of cells in the S- and G2/M phase decreased. Interestingly, knock-down of CCND1 changed the perinuclear localization of mitochondria into a homogeneous distribution within the cytosol. In addition CCND1 knock-down led to an increase of the intracellular ATP level indicating that cyclin D1 reduced mitochondrial activity. Our findings suggest that in addition to its role in cell cycle regulation, the Wnt target gene CCND1 regulates mitochondrial localization and inhibits mitochondrial activity in colorectal cancer cells.
Highlights
Because only a few Wnt target genes are universal across cell types [3], CCND1 had to be confirmed as Wnt/β-catenin target gene in the chosen model cell line
Is responsible for mediating downstream effects on proliferation and metabolism of constitutively active Wnt signaling in colorectal cancer cells
In order to investigate the impact of the Wnt target cyclin D1 on proliferation, cell cycle progression was investigated by propidium iodide staining and flow cytometry
Summary
The Wnt pathway controls several different cellular processes and mutations in com-. Ponents of the Wnt pathway are frequently found in solid cancers [1]. The Wnt pathway regulates pluripotency in stem cells and cancer stem cells [2]. Key event of the canonical Wnt pathway is the regulation of the level of the free proto-oncoprotein β-catenin which is encoded by CTNNB1. In a cell with an inactive Wnt pathway, the β-catenin level is kept low, whereas in the Wnt-activated cell β-catenin is stabilized, accumulates in the cytoplasm and translocates into the nucleus. Nuclear β-catenin forms a complex with transcription factors of the T-cell factor/Lymphoid enhancer factor (TCF/LEF) family, which activates transcription of many different target genes [3] [4]. A detailed list of the Wnt target genes can be found on the Wnt homepage [5]
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