CaV channels and cancer: canonical functions indicate benefits of repurposed drugs as cancer therapeutics

Abstract

The importance of ion channels in the hallmarks of many cancers is increasingly recognised. This article reviews current knowledge of the expression of members of the voltage-gated calcium channel family (Ca_V) in cancer at the gene and protein level and discusses their potential functional roles. The ten members of the Ca_V channel family are classified according to expression of their pore-forming α-subunit; moreover, co-expression of accessory α2δ, β and γ confers a spectrum of biophysical characteristics including voltage dependence of activation and inactivation, current amplitude and activation/inactivation kinetics. Ca_V channels have traditionally been studied in excitable cells including neurones, smooth muscle, skeletal muscle and cardiac cells, and drugs targeting the channels are used in the treatment of hypertension and epilepsy. There is emerging evidence that several Ca_V channels are differentially expressed in cancer cells compared to their normal counterparts. Interestingly, a number of Ca_V channels also have non-canonical functions and are involved in transcriptional regulation of the expression of other proteins including potassium channels. Pharmacological studies show that Ca_V canonical function contributes to the fundamental biology of proliferation, cell-cycle progression and apoptosis. This raises the intriguing possibility that calcium channel blockers, approved for the treatment of other conditions, could be repurposed to treat particular cancers. Further research will reveal the full extent of both the canonical and non-canonical functions of Ca_V channels in cancer and whether calcium channel blockers are beneficial in cancer treatment.

Keywords: Calcium channels; Cancer; Repurposed drugs.

Fig. 1

Schematic of potential mechanisms of Ca_V channels in cancer. In many cancers, expression and function of Ca_V channels is altered. There is compelling evidence that altered Ca_V expression and function contributes to several cancer hallmarks including proliferation, apoptotic resistance, migration, invasion and enhanced cell survival. These can arise through Ca²⁺-dependent signalling pathways via influx of Ca²⁺ through the Ca_V membrane channels. In addition, non-canonical signalling occurs, particularly in Ca_V1.2 and Ca_V1.3 where proteolytic cleavage of the c terminus produces a fragment that translocates to the nucleus and regulates the transcription of genes involved in processes of tumour development and progression