Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis

Abstract

Plasma membrane potassium (K+) channels are required for tumor cell proliferation and apoptosis. However, the signal transduction mechanisms underlying K+ channel-dependent tumor cell proliferation or apoptosis remains elusive. Using HeLa and A2780 cells as study models, we tested the hypothesis that apoptotic proteins are linked with K+ channel-dependent tumor cell cycle and apoptosis. The patch-clamping study using the whole-cell mode revealed two components of voltage-gated outward K+ currents: one is sensitive to either tetraethylammonium (TEA) or tetrandrine (Tet), a maxi-conductance Ca2+-activated K+ (BK) channel blocker, and the other is sensitive to 4-aminopyridine (4-AP), a delayed rectifier K+ channel blocker. MTT and flow cytometry assays showed that TEA, Tet, or iberiotoxin (Ibtx), a selective BK channel blocker, inhibited HeLa and A2780 cell proliferation in a dose-dependent manner with G1 phase arrest. Pretreatment with TEA or Tet also induced apoptosis in HeLa and A2780 cells. However, glibenclamide (Gli), an ATP-sensitive K+ channel blocker, did not influence K+ currents, proliferation or apoptosis. Western blot analyses showed that while pretreatment of TEA and Tet produced an increase in expressions of p53, p21, and Bax, pretreatment of these two agents led to a decrease in expressions of heat shock protein (hsp)90alpha, hsp90beta, and hsp70. Our results indicate that the blockade of BK channels results in tumor cell apoptosis and cycle arrest at G1 phase, and the transduction pathway underlying the anti-proliferative effects is linked to the increased expression of apoptotic protein p53 and the decreased expression of its chaperone proteins hsp.

Activity of BKCa Channel Is Modulated by Membrane Cholesterol Content and Association with Na+/K+-ATPase in Human Melanoma IGR39 Cells

“…The effects of BK channel activity on cell proliferation may be mediated either by K ϩ currents per se or by a transmembrane Ca 2ϩ influx to which the BK Ca channel could contribute by hyperpolarizing the membrane thus increasing the driving force for Ca 2ϩ entry (31,32,(65)(66)(67). The downstream pathways are not well know, but in the latter case a rise in [Ca 2ϩ ] i activates transcription factors regulating the cell cycle (64,68) and may also serve as a positive feedback loop further activating the BK Ca channels. Fig.…”

Ethanol Modulates BKCaChannels by Acting as an Adjuvant of Calcium

“…On the other hand, overall Ca i 2ϩ in neurons can reach several tens of micromolar during pathophysiological processes, including excitotoxicity, seizures, and aging (Tymianski and Tator, 1996). At these Ca i 2ϩ levels, ethanol will inhibit BK Ca channels, impairing one of the major channel populations that protects a cell from toxic Ca i 2ϩ levels (Han et al, 2007).…”

Ion channels and apoptosis in cancer

“…While direct intervention at the level of ion channels can be beneficial, indirect consequences of channel inhibition can also sensitize tumour cells to apoptosis. Indirect inhibition of large-conductance Ca 2þ -activated potassium channels (BK channels) in HeLa and A2780 cancer cells induced tumour cell apoptosis [107]. Although counterintuitive to the efflux of intracellular potassium, the mechanism of apoptotic activation via potassium channel inhibition in these cells occurred via increased p53, p21 and Bax expression.…”