NON-CARDIAC CLINICAL SYNDROMES WHERE hERG MAY BE A TARGET

Leukaemias and Other Cancers

Evidence is amassing that hERG plays a role in numerous forms of cancer [Arcangeli, 2005].  hERG channel transcripts are over-expressed in many types of human cancers, including endometrial [Cherubini et al., 2000] and colorectal adenocarcinomas [Lastraioli et al., 2004], as well as acute myeloid [Hofmann et al., 2001a; Pillozzi et al., 2002] and lymphoid leukemias [Smith et al., 2002], whereas it is not expressed in the corresponding normal cells or in benign neoplastic lesions such as endometrial hyperplasias [Cherubini et al., 2000] and most colorectal adenomas [Lastraioli et al., 2004].  Presumably this is caused by hERG regulating the resting membrane potential Vm of non-excitable cells, especially cycling cells such as tumours [Bianchi et al., 1998].  Cell cycle-dependent changes in the expression of other members of the hERG family (including hERG2, hERG3 and hERG1b) have been observed in tumour cell lines [Crociani et al., 2003], and CD34+-enriched peripheral blood mononuclear cells did not express hERG1 unless the cells were induced with cytokines and entered S phase of the cell cycle [Pillozzi et al., 2002].  The implication is that hERG activity is responsible for proliferation, and this has been functionally supported by evidence using pharmacological blockers of hERG [Pillozzi et al., 2002; Smith et al., 2002].  In addition there is evidence that hERG may play a role in tumour cell invasiveness [Lastraioli et al., 2004], which is presumably linked to the functional association between hERG1 channels and b1 integrins in neoplastic cells [Hofmann et al., 2001b].  Finally, hERG may even regulate neoangiogenesis, as blockade of hERG significantly impairs secretion of the angiogenic factor VEGF in hERG-expressing glioblastoma cells [Masi et al., 2005].

Muscle Wasting

Skeletal muscle atrophy is a debilitating reduction of muscle strength and contractile protein that can be caused by disease, disuse, muscle damage, or aging [Glass, 2003], and the current therapies for skeletal muscle atrophy are inadequate.  There has been a recent report that one of the mouse homologues of hERG, Merg1a, may be causally involved in mediating skeletal muscle atrophy induced by either neoplasm or inactivity [Wang et al., 2006].  Merg1a is up-regulated in skeletal muscle tissue before atrophy is observed when atrophy is induced by muscle inactivity, and inducing ectopic Merg1a expression can lead to skeletal muscle atrophy.  The mechanism seems to involve a Merg1a-specific induction of protein degradation by the ubiquitin proteasome pathway.  Most importantly, the induced atrophy can be prevented by treatment with the high affinity hERG-blocker astemizole, suggesting that hERG may be a clinically relevant target for this disorder.

 

References

Arcangeli A (2005). Expression and role of hERG channels in cancer cells. Novartis. Found. Symp. 266:225-232.
Bianchi L, Wible B, Arcangeli A, Taglialatela M, Morra F, Castaldo P, Crociani O, Rosati B, Faravelli L, Olivotto M, Wanke E (1998). herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells? Cancer Res. 58:815-822.
Cherubini A, Taddei GL, Crociani O, Paglierani M, Buccoliero AM, Fontana L, Noci I, Borri P, Borrani E, Giachi M, Becchetti A, Rosati B, Wanke E, Olivotto M, Arcangeli A (2000). HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium. Br. J. Cancer 83:1722-1729.
Crociani O, Guasti L, Balzi M, Becchetti A, Wanke E, Olivotto M, Wymore RS, Arcangeli A (2003). Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells. J. Biol. Chem. 278:2947-2955.
Glass DJ (2003). Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat. Cell Biol. 5:87-90.
Hofmann G, Bernabei PA, Crociani O, Cherubini A, Guasti L, Pillozzi S, Lastraioli E, Polvani S, Bartolozzi B, Solazzo V, Gragnani L, Defilippi P, Rosati B, Wanke E, Olivotto M, Arcangeli A (2001a). HERG K+ channels activation during beta(1) integrin-mediated adhesion to fibronectin induces an up-regulation of alpha(v)beta(3) integrin in the preosteoclastic leukemia cell line FLG 29.1. J. Biol. Chem. 276:4923-4931.
Hofmann G, Bernabei PA, Crociani O, Cherubini A, Guasti L, Pillozzi S, Lastraioli E, Polvani S, Bartolozzi B, Solazzo V, Gragnani L, Defilippi P, Rosati B, Wanke E, Olivotto M, Arcangeli A (2001b). HERG K+ channels activation during beta(1) integrin-mediated adhesion to fibronectin induces an up-regulation of alpha(v)beta(3) integrin in the preosteoclastic leukemia cell line FLG 29.1. J. Biol. Chem. 276:4923-4931.
Lastraioli E, Guasti L, Crociani O, Polvani S, Hofmann G, Witchel H, Bencini L, Calistri M, Messerini L, Scatizzi M, Moretti R, Wanke E, Olivotto M, Mugnai G, Arcangeli A (2004). herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells. Cancer Res. 64:606-611.
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Pillozzi S, Brizzi MF, Balzi M, Crociani O, Cherubini A, Guasti L, Bartolozzi B, Becchetti A, Wanke E, Bernabei PA, Olivotto M, Pegoraro L, Arcangeli A (2002). HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors. Leukemia 16:1791-1798.
Smith GA, Tsui HW, Newell EW, Jiang X, Zhu XP, Tsui FW, Schlichter LC (2002). Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells. J. Biol. Chem. 277:18528-18534.
Wang X, Hockerman GH, Green HW, III, Babbs CF, Mohammad SI, Gerrard D, Latour MA, London B, Hannon KM, Pond AL (2006). Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway. FASEB J. 20:1531-1533.