Physical and Functional Interaction between Integrins and hERG1 Channels in Cancer Cells

Abstract

Cancer is a complex multistep disease characterized by a profound genetic instability which leads to the aberrant and uncoordinated expression of several gene products, ultimately leading to the acquisition of a malignant phenotype. The identification of molecules and pathways that contribute to cancer establishment and progression has determined an enormous progress in oncology, providing new perspectives for the design of more specific and efficacious pharmacological approaches. In this picture, ion channels represent a relatively novel and unexpected player. In fact, the expression and activity of different channel types mark and regulate specific stages of cancer progression. The contribution of ion channels to the neoplastic phenotype ranges from the control of cell proliferation and apoptosis, to the regulation of invasiveness and metastatic spread. The role of ion channels in such processes can often be attributed to novel signaling mechanisms triggered and modulated by ion channel proteins, independently from ion fluxes. Ion channels encoded by the human ether-a-go-go-related gene 1 (herg), hERG 1 channels, are often aberrantly expressed in many primary human cancers and exert pleiotropic effects in cancer cells. Some of them are strictly related to the modulation of adhesive interactions with the extracellular matrix. The latter in turn can either regulate cell differentiation, or improve cell motility and invasiveness or stimulate the process of neo-angiogenesis. hERG1 channels can induce such diverse effects since they trigger and modulate intracellular signaling cascades. This role often depends on the formation, on the plasma membrane of tumor cells, of macromolecular complexes with membrane receptors, especially integrins. The link between hERG1 and integrins is twofold: integrins, mainly the beta1 integrin subunit, can activate hERG1. Conversely, the channels, once activated by integrins, can modulate signaling pathways downstream to integrin receptors. Both effects are mediated by the formation of a hERG1/beta1 integrin complex. Based on current evidence, we hypothesize that the activity of hERG1 channels inside the complex modulates the function of the partner protein(s) mainly through conformational coupling, instead of alterations of ion flow. Moreover, the hERG1-centered plasma membrane complexes, being specific of cancer cells, could represent novel targets for antineoplastic therapy.