Opioid growth factor regulates the cell cycle of human neoplasias

The native opioid growth factor (OGF), [Met(5)]enkephalin, is a tonic inhib itory peptide that modulates cell proliferation and migration, as well as t issue organization, during development, cancer, homeostatic cellular renewa l, wound healing, and angiogenesis. OGF action is mediated by the OGF recep tor (OCFr). To investigate the target of OGF as to cell proliferation, the effects of excess OGF, and a deprivation of OGF-OGFr interaction by an opio id antagonist, naltrexone (NTX), were examined in 3 human cancer cell lines : pancreatic (BxPC-3), colon (HT-29), and head and neck (CAL-27). OGF expos ure decreased growth, DNA synthesis, and mitosis, and increased the doublin g time from control levels. FAGS analysis revealed a marked increase in cel ls in the G(0)/G(1), phase and compensatory reduction in cells in S and G(2 )/M phases. Consistent with this observation, the percentage of labeled mit osis (PLM) analysis showed a notable increase in the time of the G(0)/G(1) phase. Receptor blockade with NTX increased the rate of growth, length of D NA synthesis and mitotic phases, and decreased doubling time from control v alues. FAGS analysis indicated an increase in the proportion of cells in S and G(2)/M phases, and a decrease in the number of cells in the G(0)/G(1) p hase. PLM evaluation demonstrated a shortening of the length of the S and G (2) phases in the 3 cell lines, and decreases in the M and G(0)/G(1) phases in some cancers. These results indicate that OGF action is directed at the G(0)/G(1) phase, but interruption of OGF-OGFr interfacing has widespread r epercussions on the cell cycle. The data on blockade of OGF-OGFr during log phase growth suggest a requisite escorting of the growth peptide and its r eceptor through the cell cycle.