Hypoxia-Inducible Factor 1α and AT-Rich Interactive Domain-Containing Protein 1A Expression in Pituitary Adenomas: Association with Pathological, Clinical, and Radiological Features

Kınalı, Burak; Şenoğlu, Mehmet; Karadağ, Fatma Keklik; Middlebrooks, Erik H.; Öksüz, Pınar; Sandal, Evren; Turk, Caglar; Diniz, Gülden

doi:10.1016/j.wneu.2018.09.196

Cited by 4 publications

(3 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activity of K V channels (e.g., eag1-mediated K + channels) has been noted to be associated with oxygen homeostats and induction of angiogenesis in certain types of tumors [17]. Of particular interest, the HIF-1α expression in pituitary gland including pituitary tumor (GH 3 ) cells has shown that it is closely linked to the occurrence or progression of pituitary adenoma [16,18,19,20,21,22,23,24].…”

Section: Introductionmentioning

confidence: 99%

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

Chang

Gao

et al. 2019

IJMS

View full text Add to dashboard Cite

Roxadustat (FG-4592), an analog of 2-oxoglutarate, is an orally-administered, heterocyclic small molecule known to be an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase. However, none of the studies have thus far thoroughly investigated its possible perturbations on membrane ion currents in endocrine or heart cells. In our studies, the whole-cell current recordings of the patch-clamp technique showed that the presence of roxadustat effectively and differentially suppressed the peak and late components of IK(DR) amplitude in response to membrane depolarization in pituitary tumor (GH3) cells with an IC50 value of 5.71 and 1.32 μM, respectively. The current inactivation of IK(DR) elicited by 10-sec membrane depolarization became raised in the presence of roxadustatt. When cells were exposed to either CoCl2 or deferoxamine (DFO), the IK(DR) elicited by membrane depolarization was not modified; however, nonactin, a K+-selective ionophore, in continued presence of roxadustat, attenuated roxadustat-mediated inhibition of the amplitude. The steady-state inactivation of IK(DR) could be constructed in the presence of roxadustat. Recovery of IK(DR) block by roxadustat (3 and 10 μM) could be fitted by a single exponential with 382 and 523 msec, respectively. The roxadustat addition slightly suppressed erg-mediated K+ or hyperpolarization-activated cation currents. This drug also decreased the peak amplitude of voltage-gated Na+ current with a slowing in inactivation rate of the current. Likewise, in H9c2 heart-derived cells, the addition of roxadustat suppressed IK(DR) amplitude in combination with the shortening in inactivation time course of the current. In high glucose-treated H9c2 cells, roxadustat-mediated inhibition of IK(DR) remained unchanged. Collectively, despite its suppression of HIF prolyl hydroxylase, inhibitory actions of roxadustat on different types of ionic currents possibly in a non-genomic fashion might provide another yet unidentified mechanism through which cellular functions are seriously perturbed, if similar findings occur in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

Chang

Gao

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…The perturbations by PT-2385 of membrane ionic currents shown here tend to be acute in onset. Hence, the actions could be unlinked to its interaction with the activity of HIF-2α, as stated recently [9,12,14,25]. Both the steady-state inactivation curve of I K(DR)…”

Section: Discussionmentioning

confidence: 96%

“…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 ]. Alternatively, HIF-2α has also been reported to be expressed in pituitary tumors [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Effective Perturbations of the Amplitude, Gating, and Hysteresis of IK(DR) Caused by PT-2385, an HIF-2α Inhibitor

Hsiao

Liu

et al. 2021

Membranes

View full text Add to dashboard Cite

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.

show abstract

Pathophysiology of blood-brain barrier in brain tumor. Novel therapeutic advances using nanomedicine

Sharma

Mureșanu

Castellani

et al. 2020

International Review of Neurobiology

View full text Add to dashboard Cite

Hypoxia-Inducible Factor 1α and AT-Rich Interactive Domain-Containing Protein 1A Expression in Pituitary Adenomas: Association with Pathological, Clinical, and Radiological Features

Cited by 4 publications

References 39 publications

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

Effective Perturbations of the Amplitude, Gating, and Hysteresis of IK(DR) Caused by PT-2385, an HIF-2α Inhibitor

Pathophysiology of blood-brain barrier in brain tumor. Novel therapeutic advances using nanomedicine

Contact Info

Product

Resources

About