Elsevier

Cell Calcium

Volume 40, Issue 2, August 2006, Pages 253-259
Cell Calcium

T-type calcium channels and tumor proliferation

https://doi.org/10.1016/j.ceca.2006.04.029Get rights and content

Abstract

The role of T-type Ca2+ channels in proliferation of tumor cells is reviewed. Intracellular Ca2+ is important in controlling proliferation as evidenced by pulses, or oscillations, of intracellular Ca2+ which occur in a cell cycle-dependent manner in many tumor cells. Voltage-gated calcium channels, such as the T-type Ca2+ channel, are well suited to participate in such oscillations due to their unique activation/inactivation properties. Expression of the T-type Ca2+ channels has been reported in numerous types of tumors, and has been shown to be cell cycle-dependent. Overexpression of the α1 subunit of T-type Ca2+ channels in human astrocytoma, neuroblastoma and renal tumor cell lines enhanced proliferation of these cells. In contrast, targeting of the α1 subunit of the T-type calcium channel via siRNA decreased proliferation of these cells. A Ca2+ oscillatory model is proposed involving potassium channels, Ca2+ stores and Ca2+ exchangers/transporters. A review of T-type channel blockers is presented, with a focus on mibefradil-induced inhibition of proliferation. The development of newer blockers with higher selectivity and less potential side effects are discussed. The conclusion reached is that calcium channel blockers serve as a potential therapeutic approach for tumors whose proliferation depends on T-type calcium channel expression.

Section snippets

Introduction — role of calcium in proliferation

Proliferation of tumors and non-tumor cells, is regulated, in part, by the second messenger calcium (Ca2+) [1], [2]. Ca2+ is an important activator or inhibitor of numerous intracellular enzymes in the cytosol, organelles and nucleus. Many of these effects of intracellular Ca2+ are mediated through its binding with calmodulin, which in turn controls different kinases, phosphatases, cyclases, esterases, as well as ion channels. Protoplasmic Ca2+ levels are regulated by several mechanisms

Distribution of T-type Ca2+ channels in proliferating tissue

T-type Ca2+channels are expressed in several different types of tumors or tumor cell lines as well as in normal tissue throughout the body, including brain, heart, kidney, and smooth muscle. A role for T-type Ca2+ channels in proliferation has been reported in breast tumors [5], [6], brain tumors [7], [8], colorectal tumors [9], gastric tumors [9], leukemic cells [9], prostate tumors [10], [11], [12], retinoblastoma cells [13], [14], [15] and pheochromocytoma cells lines (PC12) [16].

Although

Role of the T-type Ca2+ channels in control of the cell cycle and proliferation

Variations in T-type Ca2+ channel expression have been reported as a function of the cell cycle. For example, cells in the proliferative phase (G2/M) have been reported to frequently express T-type Ca2+ channels whereas cells in the non-proliferative phases (G0/G1) express primarily L-type Ca2+ channels [25], [26]. Similar increases in expression of T-type Ca2+ channels in the proliferative phase have been reported in a variety of cells [27], [28], [29], [30].

These cell cycle-related variations

Calcium oscillator model

An issue that is not resolved is how T-type Ca2+ channel and currents are activated to produce the Ca2+ waves. One possible schematic model is illustrated in Fig. 3. The initiation of T-type Ca2+ currents is secondary to membrane potentials controlled by potassium (K+) channels [35], [36]. Depending upon the resting membrane potential of the cell, decreased or increased K+ potassium currents may increase the T-type Ca2+ current.

In hyperpolarized cells in the G0 phase of the cell cycle,

Effects of blockers of T-type Ca2+ on proliferation

The above observations suggest that the T-type Ca2+ channels might serve as a target for treatment of a number of tumors. There are a variety of agents that can affect T-type Ca2+ current with varying degrees of specificity.

For several years, mibefradil has been recognized as a “selective” T-type Ca2+ channel antagonist, although it does affect other functions, particularly at super micromolar concentrations. The mibefradil blockade of T-type Ca2+ channels is some 10–20 times more selectively

Summary

Determination of the expression and activity of T-type Ca2+ channels in specific tumors and the development of new, specific T-type Ca2+ channel blockers have the potential of offering new approaches to the treatment of some cancer patients who are no longer responsive to more conventional treatment strategies.

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