Mutations in the opioid growth factor receptor in human cancers alter receptor function

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Abstract

The opioid growth factor (OGF)-OGF receptor (OGFr) axis is present and tonically active in animal and human cancer cell lines and tumors. The OGF-OGFr pathway tonically mediates cell replication in cancer, with OGF serving as an autocrine-produced inhibitory pentapeptide. The inhibitory effect of OGF on cancer cell replication requires the binding of OGF to OGFr and its trafficking into the nucleus, where it upregulates inhibitory kinase expression, thus suppressing the cell cycle. OGF has been reported to markedly inhibit the growth of human cancer cells transplanted into nude mice, and to enhance the therapeutic effects of agents, such as paclitaxel and gemcitabine. At the time that this study commenced, there were 13 missense mutations identified in OGFr that had been curated in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Little is known about any mutations identified in OGFr or how mutated OGFr may alter the inhibitory activity of OGF. In this study, two mutations identified in cancer samples, S378I and R444H, were characterized with respect to how they modified OGFr trafficking into the nucleus and changed the functional attributes of DNA synthesis. R444H demonstrated a significant decrease in the nuclear/cytoplasmic ratio, while S378I showed no change. Both mutations demonstrated a loss of response to OGF and the long-acting opioid antagonist, naltrexone (NTX), while only R444H showed a loss of inhibition in the 5-bromo-2′-deoxyuridine (BrdU) assay. These data demonstrate that an intact OGFr is required for a full response to biotherapy with OGF, and that it is important to characterize potential mutations in neoplasia which could affect therapeutic responsiveness.

Original languageEnglish (US)
Pages (from-to)289-293
Number of pages5
JournalInternational journal of molecular medicine
Volume36
Issue number1
DOIs
StatePublished - Jul 1 2015

All Science Journal Classification (ASJC) codes

  • Genetics

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