Intracellular calcium oscillations in strongly metastatic human breast and prostate cancer cells: control by voltage-gated sodium channel activity

Abstract

The possible association of intracellular Ca²⁺ with metastasis in human cancer cells is poorly understood. We have studied Ca²⁺ signaling in human prostate and breast cancer cell lines of strongly versus weakly metastatic potential in a comparative approach. Intracellular free Ca²⁺ was measured using a membrane-permeant fluorescent Ca²⁺-indicator dye (Fluo-4 AM) and confocal microscopy. Spontaneous Ca²⁺ oscillations were observed in a proportion of strongly metastatic human prostate and breast cancer cells (PC-3M and MDA-MB-231, respectively). In contrast, no such oscillations were observed in weakly/non metastatic LNCaP and MCF-7 cells, although a rise in the resting Ca²⁺ level could be induced by applying a high-K⁺ solution. Various parameters of the oscillations depended on extracellular Ca²⁺ and voltage-gated Na⁺ channel activity. Treatment with either tetrodotoxin (a general blocker of voltage-gated Na⁺ channels) or ranolazine (a blocker of the persistent component of the channel current) suppressed the Ca²⁺ oscillations. It is concluded that the functional voltage-gated Na⁺ channel expression in strongly metastatic cancer cells makes a significant contribution to generation of oscillatory intracellular Ca²⁺ activity. Possible mechanisms and consequences of the Ca²⁺ oscillations are discussed.

Keywords: Calcium oscillation; Metastasis; Persistent current; Ranolazine; Tetrodotoxin; Voltage-gated sodium channel.