HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential

He, Siyi; Moutaoufik, Mohamed Taha; Islam, Saadul; Persad, A; Wu, Adam; Aly, Khaled A.; Fonge, Humphrey; Babu, Mohan; Cayabyab, Francisco S.

doi:10.1016/j.bbcan.2020.188355

Cited by 46 publications

(40 citation statements)

References 172 publications

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“…Non-arrhythmogenic hERG inhibitors, which block hERG without inducing arrhythmia, can improve the survival rate among glioblastoma patients showing high hERG expression [ 13 ]. These clinical results demonstrate the therapeutic potential of the specific ligands controlling hERG function; thus, it is of great medical importance to determine the structural mechanisms underlying the interactions between hERG and its specific ligands [ 3 , 12 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

Matsumura

Shimomura

Kubo

et al. 2021

BMC Mol and Cell Biol

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Background Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Results We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis. Conclusions The present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of KV channels.

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Section: Introductionmentioning

confidence: 99%

Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

Matsumura

Shimomura

Kubo

et al. 2021

BMC Mol and Cell Biol

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“…Non-arrhythmogenic hERG inhibitors, which block hERG without inducing arrhythmia, can improve the survival rate among glioblastoma patients showing high hERG expression ( Pointer et al, 2017 ). These clinical results demonstrate the therapeutic potential of the specific ligands controlling hERG function; thus, it is of great medical importance to determine the structural mechanisms underlying the interactions between hERG and its specific ligands ( Arcangeli and Becchetti, 2017; He et al, 2020; Vandenberg et al, 2012 ).…”

Section: Introductionmentioning

confidence: 85%

“…This function is necessary for a normal heartbeat, as demonstrated by the fact that some hERG inhibitors cause lethal arrhythmia accompanied by long QT syndrome ( Curran et al, 1995; Roden, 2004; Sanguinetti et al, 1995; Sanguinetti and Tristani-Firouzi, 2006 ). Recently, it has been reported that variations in the gene encoding hERG are associated with schizophrenia ( Apud et al, 2012; Atalar et al, 2010; Huffaker et al, 2009 ), and that alterations in hERG expression and function are observed in various types of cancer cells and are involved in carcinogenic processes ( He et al, 2020; Jehle et al, 2011; Rao et al, 2015 ). Non-arrhythmogenic hERG inhibitors, which block hERG without inducing arrhythmia, can improve the survival rate among glioblastoma patients showing high hERG expression ( Pointer et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

Matsumura

Shimomura

Kubo

et al. 2020

Preprint

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Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. Although it is known that APETx1 inhibits hERG by stabilizing the resting state, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Here, we prepared a recombinant APETx1, which is structurally and functionally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, in addition to a previously reported acidic hERG residue, play key roles in the inhibition of hERG by APETx1. Docking models of the APETx1-VSD complex that satisfy the results of mutational analysis suggest a molecular recognition mode between APETx1 and the resting state of hERG; this would provide a structural basis for designing ligands that control hERG function by binding to the VSD.

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“…Kv10.1 was proposed to be crucially involved in the resorption of the primary cilium during the G2/M phase of the cell cycle, thus favoring cell cycle progression (Urrego et al, 2017). As to Kv11.1, this channel has been associated to different tumoral processes such as cell cycle progression, angiogenesis, invasiveness and metastasis formation and the channel is also overexpressed in a variety of cancer cells with respect to corresponding non-cancer tissues (He S. et al, 2020). Indeed, implications of Kv11.1 on cell FIGURE 2 | Kv1.3 regulates T lymphocyte proliferation: the «membrane potential model».…”

Section: Kv10 and Kv11 Channelsmentioning

confidence: 99%

Voltage-Gated Potassium Channels as Regulators of Cell Death

Bachmann

Edwards

et al. 2020

Front. Cell Dev. Biol.

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Ion channels allow the flux of specific ions across biological membranes, thereby determining ion homeostasis within the cells. Voltage-gated potassium-selective ion channels crucially contribute to the setting of the plasma membrane potential, to volume regulation and to the physiologically relevant modulation of intracellular potassium concentration. In turn, these factors affect cell cycle progression, proliferation and apoptosis. The present review summarizes our current knowledge about the involvement of various voltage-gated channels of the Kv family in the above processes and discusses the possibility of their pharmacological targeting in the context of cancer with special emphasis on Kv1.1, Kv1.3, Kv1.5, Kv2.1, Kv10.1, and Kv11.1.

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HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential

Cited by 46 publications

References 172 publications

Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

Voltage-Gated Potassium Channels as Regulators of Cell Death

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