Evidence for an early G1 ionic event necessary for cell cycle progression and survival in the MCF-7 human breast carcinoma cell line

Abstract

The mechanism of the G0/G1 arrest and inhibition of proliferation by quinidine, a potassium channel blocker, was investigated in a tissue culture cell line, MCF-7, derived from a human breast carcinoma. The earliest measurable effect of quinidine on the cell cycle was a decrease in the fraction of cells in S phase at 12 hr, followed by the accumulation of cells in G1/G0 phases at 30 hr. Arrest and release of the cell cycle established quinidine as a cell synchronization agent, with a site of arrest in early G1 preceding the lovastatin G1 arrest site by 5-6 hr. There was a close correspondence among the concentration-dependent arrest by quinidine in G1, depolarization of the membrane potential, and the inhibition of ATP-sensitive potassium currents, supporting a model in which hyperpolarization of the membrane potential and progression through G1 are functionally linked. Furthermore, the G1 arrest by quinidine was overcome by valinomycin, a potassium ionophore that hyperpolarized the membrane potential in the presence of quinidine. With sustained exposure of MCF-7 cells to quinidine, expression of the Ki67 antigen, a marker for cells in cycle, decreased, and apoptotic and necrotic cell death ensued. We conclude that MCF-7 cells that fail to progress through the quinidine-arrest site in G1 die.

Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells

“…These biophysical properties are not simply markers but are functional signals; misexpression of an ion transporter induces tumorigenicity in fibroblasts (50), and inhibition of EAG channel function suppresses neoplasm in an animal model in vivo (51). Ion channel function controls the proliferation rate and invasiveness of a number of cell types that often form tumors (49,(52)(53)(54)(55), and overexpression of KCNK9 (strongly overexpressed in breast cancer) promotes tumor formation and confers resistance to hypoxia and serum deprivation (56). Misexpression of KCNE1 did not induce tumors per se.…”

Blockage of intermediate-conductance-Ca2+-activated K+ channels inhibits progression of human endometrial cancer

“…Our findings that clotrimazole or TRAM-34 blocked the IKCa1 current and cell proliferation in HEC-1-A cells are consistent with this explanation. It has been known that cells in the early G 1 phase are depolarized; however, they are hyperpolarized during the progression through G 1 into the S phase (Wang et al, 1998;Ghanshani et al, 2000). Inhibition of K þ channels leads to membrane depolarization and cellcycle arrest in early G 1 phase in the MCF-7 human breast carcinoma cell line (Wang et al, 1998).…”

“…It has been known that cells in the early G 1 phase are depolarized; however, they are hyperpolarized during the progression through G 1 into the S phase (Wang et al, 1998;Ghanshani et al, 2000). Inhibition of K þ channels leads to membrane depolarization and cellcycle arrest in early G 1 phase in the MCF-7 human breast carcinoma cell line (Wang et al, 1998). Conversely, activation of K þ channels promotes the cellcycle progression from the G 0 /G 1 to S phase (Wonderlin et al, 1995;Ouadid-Ahidouch et al, 2001;Chittajallu et al, 2002).…”

Rapid Induction of Histone Hyperacetylation and Cellular Differentiation in Human Breast Tumor Cell Lines following Degradation of Histone Deacetylase-1

“…Previous studies with human breast tumor cell lines demonstrated that quinidine (90 M) is an anti-proliferative agent as well. Quinidine arrested cells in early G 1 phase and induced apoptosis by 72-96 h in MCF-7 cells (12), but the biochemical basis for the anti-proliferative effect of quinidine was not well understood. To clarify the molecular mechanisms of the antiproliferative activity of quinidine, we investigated the effects of quinidine on histone acetylation and cell cycle regulatory proteins.…”