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ENOX2 (tNOX) and Cancer

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ECTO-NOX Proteins

Abstract

ENOX2 or tNOX (for tumor-associated NOX) proteins are ENOX proteins specific to cancer. Demonstrated to be present in several human tumor tissues, serum analyses of shed ENOX2 proteins suggest a much broader, perhaps universal association with human cancer. ENOX2 proteins are cell surface-located but differ from ENOX1 proteins in their response to inhibitors, activators and drugs, amino acid sequence, functional motifs, period length of oscillatory activities (22 min), and entrainment properties. Unique to ENOX2 proteins is their sensitivity to inhibition by quinone site inhibitors with anticancer activity such as capsaicin, doxorubicin, antitumor sulfonylureas, the catechin (−)-epigallocatechin-3-gallate and the anticancer isoflavene, phenoxodiol. The shed forms exhibit the same degree of drug responsiveness as the cell membrane-associated forms. They do not normally respond to growth factors and are constitutively activated. As such, the presence of ENOX2 proteins correlated with the unregulated growth that characterizes the cancer phenotype. ENOX proteins are not the result of oncogenic mutations and may be of onco-fetal origins but lost in adults. The basis for cancer specificity of ENOX2 expression at the cells surface is traced to alternative splicing with the generation of an exon 4 minus form present in cancer cell lines and absent in non-cancer cell lines. The exon 4 minus form results in initiation of translation at a downstream M231 initiation site and is permissive for delivery of mature and fully processed ENOX2 protein to the cancer cell surface. Exonic Splicing Factor hnRNP F has been shown to direct formation of the exon 4 minus splice variant. The first ENOX protein to be cloned and expressed, the ENOX2 gene consists of a least nine exons. ENOX2 proteins exhibit disulfidethiol interchange activity despite the absence of flavin and only one –C–X–X–X–X–C– motif characteristic of classical protein disulfide isomerases. The drug binding site contains a conserved five amino acid (EMTEE) motif absent from ENOX1. Protease resistance and multimerization to form amyloid are characteristics shared with prions. The phenotypic characteristic of formation of colonies on soft agar associated with cancer is lost for HeLa cells transfected with exon 5 antisense two-dimensional gel electrophoresis/western blot analysis reveal more than ten ENOX2 transcript variants, each with specific molecular weights and isoelectric points and each characteristic of a specific organ site with potential for very early diagnosis of cancer that affords opportunities for early intervention.

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Morré, D.J., Morré, D.M. (2012). ENOX2 (tNOX) and Cancer. In: ECTO-NOX Proteins. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3958-5_8

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