CACNA2D2 promotes tumorigenesis by stimulating cell proliferation and angiogenesis

Abstract

In the present study, we have assessed whether a putative calcium channel α2δ2 auxiliary subunit (CACNA2D2 gene) could be involved in prostate cancer (PCA) progression. We therefore carried out experiments to determine whether this protein is expressed in PCA LNCaP cells and in PCA tissues, and whether its expression may be altered during cancer development. In addition, we evaluated the influence on cell proliferation of overexpressing or downregulating this subunit. In vitro experiments show that α2δ2 subunit overexpression is associated with increased cell proliferation, alterations of calcium homeostasis and the recruitment of a nuclear factor of activated T-cells pathway. Furthermore, we carried out in vivo experiments on immuno-deficient nude mice in order to evaluate the tumorigenic potency of the α2δ2 subunit. We show that α2δ2-overexpressing PCA LNCaP cells are more tumorigenic than control LNCaP cells when injected into nude mice. In addition, gabapentin, a ligand of α2δ2, reduces tumor development in LNCaP xenografts. Finally, we show that the action of α2δ2 on tumor development occurs not only through a stimulation of proliferation, but also through a stimulation of angiogenesis, via an increased secretion of vascular endothelial growth factor in cells overexpressing α2δ2.

Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma

“…Several of the genes, such as Mmp8, Dock10, Hoxd3 and Fat3 , have previously been reported to show mutation or altered expression in cancer and particularly metastasis [41–45]. Two genes, Cacna2d2 and Dbc1 are candidate tumour suppressors in other cancers [46, 47]. …”

“…However, in the mouse genome, the orthologs reside on different chromosomes. The importance of this gene in MM in undetermined, though it has been linked to tumorigenesis in prostate cancer [46] and loss of expression has been demonstrated in non-small cell lung cancer [54]. …”

Identification of common and distinct epigenetic re-programming properties of Core-Binding Factor (CBF) Fusion Proteins

“…CACNA2D2 encodes a voltage gated calcium channel, which when mutated in mice leads to the development of an ataxic gait and epilepsy (Barclay et al, 2001). No studies on CACNA2D2 have been performed in AML, however, functional studies have shown both tumour suppressor activity in lung cancer (Carboni et al, 2003) and oncogenic properties in prostate cancer (Warnier et al, 2015). Overall, CACNA2D2 is thought to be a tumour suppressor gene, as it is part of a 120kb region recurrently deleted in a variety of solid tumours (Hesson et al, 2007).…”

Molecular mechanisms of tumour invasion: regulation by calcium signals

“…; Warnier et al . ). Moreover, the importance of TRPC6 as a modulator of angiogenic potential has been revealed in glioma cells (Chigurupati et al .…”