Abstract
PT-2385 is currently regarded as a potent and selective inhibitor of hypoxia-inducible factor-2α (HIF-2α), with potential antineoplastic activity. However, the membrane ion channels changed by this compound are obscure, although it is reasonable to assume that the compound might act on surface membrane before entering the cell´s interior. In this study, we intended to explore whether it and related compounds make any adjustments to the plasmalemmal ionic currents of pituitary tumor (GH3) cells and human 13-06-MG glioma cells. Cell exposure to PT-2385 suppressed the peak or late amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner, with IC50 values of 8.1 or 2.2 µM, respectively, while the KD value in PT-2385-induced shortening in the slow component of IK(DR) inactivation was estimated to be 2.9 µM. The PT-2385-mediated block of IK(DR) in GH3 cells was little-affected by the further application of diazoxide, cilostazol, or sorafenib. Increasing PT-2385 concentrations shifted the steady-state inactivation curve of IK(DR) towards a more hyperpolarized potential, with no change in the gating charge of the current, and also prolonged the time-dependent recovery of the IK(DR) block. The hysteretic strength of IK(DR) elicited by upright or inverted isosceles-triangular ramp voltage was decreased during exposure to PT-2385; meanwhile, the activation energy involved in the gating of IK(DR) elicitation was noticeably raised in its presence. Alternatively, the presence of PT-2385 in human 13-06-MG glioma cells effectively decreased the amplitude of IK(DR). Considering all of the experimental results together, the effects of PT-2385 on ionic currents demonstrated herein could be non-canonical and tend to be upstream of the inhibition of HIF-2α. This action therefore probably contributes to down-streaming mechanisms through the changes that it or other structurally resemblant compounds lead to in the perturbations of the functional activities of pituitary cells or neoplastic astrocytes, in the case that in vivo observations occur.
Highlights
hypoxia-inducible factor2α (HIF-2α) has been reported to be expressed in pituitary tumors [11]
A cause-and-effect relationship regarding the activity of KV3 or KV2 channels and the magnitude of delayed-rectifier K+ currents (IK(DR)) is correlated with action potential firing in many cell types and has increasingly been demonstrated [29,30,31,32,35,36,37,38,39,40,41,42,43,44]
Findings from the present observations tempt us to reflect that the IK(DR) inherent in different cell types could be an additional non-canonical target through which PT-2385 can act to influence the functional activities of the cells involved
Summary
Hypoxia-inducible factor-1α (HIF-1α) has been reported to be expressed in pituitary tumors [1,2,3,4,5,6,7,8,9,10]. A cause-and-effect relationship regarding the activity of KV3 or KV2 channels and the magnitude of delayed-rectifier K+ currents (IK(DR)) is correlated with action potential firing in many cell types and has increasingly been demonstrated [29,30,31,32,35,36,37,38,39,40,41,42,43,44]. Our understanding of whether PT-2385 or other related compounds cause any adjustments with regard to the amplitude, gating, and hysteresis of these types of K+ currents (e.g., IK(DR)) remains largely incomplete, recent studies have demonstrated a possible link between the expression of HIF and the regulation of KV-channel activity [23,47,48,49,50]. Findings from the present observations tempt us to reflect that the IK(DR) inherent in different cell types could be an additional non-canonical target through which PT-2385 can act to influence the functional activities of the cells involved
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