It is estimated that in 2011, 1.5 million people were diagnosed with some form of cancer and over 500,000 died of the disease.1 To improve clinical outcomes, new targets for cancer therapeutics are desirable. Towards this end, research studies in the past few decades have uncovered ion channel proteins as new targets for cancer therapy.6, 7 The Hv1 proton channel8,9 is one of the latest ion channels to emerge as a potential target for cancer diagnostics and treatment. The channel is preferentially expressed in highly metastatic human breast cancer cell lines and tumors, and appears to be essential for the cancer cell's ability to invade and metastasize.10 The channel likely contributes to cancer progression by helping to maintain the dysregulated pH gradient (high intracellular pH and low extracellular pH) characteristic of most cancers.11 The increased H+ secretion from Hv1 overexpression may aid cell survival by inhibiting acid-induced apoptosis. Furthermore, the subsequent acidification of the extracellular space stimulates acid-activated proteases to degrade the extracellular matrix, facilitating tumor cell invasion and dissemination.12 Functional blockade of Hv1 conductance in vivo and in vitro has been shown to significantly inhibit cancer progression and metastasis, highlighting channel blockade as a promising new avenue for cancer therapeutics.10 In previous studies,10,13 the functional blockade of Hv1 in vivo and in vito was achieved using RNA-interference technology. We propose, for the first time, to study small molecule blockers of Hv1 as antineoplastic therapeutics. To rationally design small molecules with high affinity for the channel, we develop a structural model for Hv1.5 Detailed atomistic structure/function data from molecular dynamics simulations of the model will address questions about how Hv1 is able to sense voltage and conduct protons, which will help to establish basic principles of ion conduction through voltage-sensing domains. Answers to these questions will guide the design of high affinity Hv1 blockers, which will be evaluated for their therapeutic potential to inhibit cancer progression using cell proliferation and migration assays. We hypothesize that these computational studies and in vitro assays will support Hv1 blockade as a viable mechanism for breast cancer cell inhibition and allow for the development of novel antineoplastic pharmaceuticals.
Cancer was the second leading cause of death in the United States in 2011, and current therapeutic strategies are still limited in scope, motivating the development of novel anticancer drugs.1 Towards this end, this project will study the Hv1 ion channel as a potential anticancer therapeutic target. Findings from this work may translate to the development of novel anticancer pharmaceuticals.
| Wood, Mona L; Freites, J Alfredo; Tombola, Francesco et al. (2017) Atomistic Modeling of Ion Conduction through the Voltage-Sensing Domain of the Shaker K+ Ion Channel. J Phys Chem B 121:3804-3812 |
| Amcheslavsky, Anna; Wood, Mona L; Yeromin, Andriy V et al. (2015) Molecular biophysics of Orai store-operated Ca2+ channels. Biophys J 108:237-46 |
