Small Molecule Binds with Lymphocyte Antigen 6K to Induce Cancer Cell Death.

Senyi Benti,Mark D Smith,Linda S Shimizu,Geeta Upadhyay,Purushottam B Tiwari,Grant B Kern,Leily Daneshian,Dustin W Goodlett,Maksymilian Chruszcz,Aykut Uren

doi:10.3390/cancers12020509

Abstract

Elevated gene expression of Lymphocyte antigen 6K (LY6K) in cancer cells is associated with poor survival outcomes in multiple different cancer types including cervical, breast, ovarian, lung, and head and neck cancer. Since inhibition of LY6K expression inhibits cancer cell growth, we set out to explore whether pharmacological inhibition of LY6K could produce the same effect. We screened small molecule libraries for direct binding to recombinant LY6K protein in a surface plasmon resonance assay. We found that NSC243928 directly binds to the full-length and mature forms of LY6K and inhibits growth of HeLa cells that express LY6K. NSC243928 did not display binding with LY6D or LY6E. Our data demonstrate a first-time proof of principle study that pharmacological inhibition of LY6K using small molecules in cancer cells is a valid approach to developing targeted therapies against LY6K. This approach will be specifically relevant in hard-to-treat cancers where LY6K is highly expressed, such as cervical, pancreatic, ovarian, head and neck, lung, gastric, and triple-negative breast cancers.

Highlights

Human Lymphocyte Antigen 6 (LY6) gene family proteins are found clustered on chromosomes 6, 8, 11, and 19 [1]
The highest Lymphocyte antigen 6K (LY6K) expression was seen in cervical, head and neck, bladder, esophageal, and breast cancer (Figure 1b)
We show that NSC243928 interacts with LY6K in a dose-dependent manner

Summary

Introduction

Human Lymphocyte Antigen 6 (LY6) gene family proteins are found clustered on chromosomes 6, 8, 11, and 19 [1]. The LY6K gene is a member of this family, located on human chromosome 8q24. Human chromosome 8q24 is often amplified in many different types of cancers and has been studied in the context of Myc overexpression, a widely known resident of genetic loci. It has been shown that genes other than Myc on 8q24 play an important role in cancer progression [5]. The expression of LY6K in normal cells is mainly found in testicular germ cells, where it plays a role in sperm cell migration [11].

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