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Opioid growth factor tonically inhibits human colon cancer cell proliferation in tissue culture
I S Zagon1, S D Hytrek, P J McLaughlin
1Department of Neuroscience and Anatomy, Pennsylvania State University, College of Medicine, Hershey 17033, USA.
Abstract:
Native opioid peptides serve as growth factors in a number of normal and neoplastic cells and tissues, including the prevention and delayed growth of human colon cancer xenografts in nude mice. This study examined the hypothesis that opioids exert a direct inhibitory influence on tumor cell growth by the use of a tissue culture model. The naturally occurring pentapeptide [Met5]enkephalin depressed growth of HT-29 human colon cancer cells from 17 to 41% at 12-72 h after administration of 10(-6)M concentration; consistent with previously defined nomenclature, this peptide was termed opioid growth factor (OGF). OGF action exhibited a dose-response relationship, was reversible and not cytotoxic, and was opioid receptor mediated. Growth inhibition by OGF was not dependent on serum, and was noted in the two other human colon cancer cell lines examined WiDr and COLO 205. This peptide continually repressed growth because an increase in cell number was noted when cells were exposed to the potent opioid antagonist naltrexone or an antibody to OGF. Both OGF and its receptor, zeta (zeta), were found in colon cancer cells by immunocytochemistry, and receptor binding assays revealed a nuclear-associated receptor with a dissociation constant of 8.9 nM and a maximum binding capacity of 43 fmol/mg of protein. OGF was produced and secreted by the tumor cells. These results lead to the suggestion that OGF has a direct, tonic, inhibitory action on the growth of human colon cancer cells and contribute to our understanding of the mechanisms underlying the marked antitumor effect of this peptide in nude mice inoculated with human colon cancer cells.
Insights
Opioid growth factor (OGF), a naturally occurring peptide, directly inhibits human colon cancer cell growth. This peptide acts on opioid receptors and is produced by tumor cells, suggesting a novel therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Native opioid peptides function as growth factors in various cells and tissues.
- Opioid peptides have demonstrated potential in preventing and delaying human colon cancer xenograft growth in mice.
Purpose of the Study:
- To investigate the direct inhibitory effect of opioids on tumor cell growth using a tissue culture model.
- To examine the role of opioid growth factor (OGF) in regulating human colon cancer cell proliferation.
Main Methods:
- Utilized HT-29 human colon cancer cells in a tissue culture model to assess OGF's impact on growth.
- Administered [Met5]enkephalin (OGF) at a concentration of 10(-6)M and monitored cell growth over 12-72 hours.
- Employed immunocytochemistry and receptor binding assays to detect OGF and its receptor (zeta) within colon cancer cells.
Main Results:
- OGF significantly depressed HT-29 colon cancer cell growth by 17-41% within 12-72 hours.
- OGF's growth inhibition was dose-dependent, reversible, non-cytotoxic, and mediated by opioid receptors.
- OGF demonstrated continuous growth repression, reversed by opioid antagonists or OGF antibodies, and was found to be produced and secreted by the tumor cells.
Conclusions:
- Opioid growth factor (OGF) exerts a direct, tonic inhibitory action on human colon cancer cell growth.
- The presence and activity of OGF and its nuclear-associated receptor in colon cancer cells support its role in tumor growth regulation.
- These findings contribute to understanding the antitumor mechanisms of OGF in colon cancer models.