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G Protein-independent G₁ Cell Cycle Block and Apoptosis with Morphine in Adenocarcinoma Cells

Involvement of p53 Phosphorylation¹

Pharmazentrum Frankfurt, Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany

Opioid effects on tumor growth have been a controversial topic of discussion. In the present study, morphine inhibited tumor cell proliferation at concentrations of 10 µM. This was primarily caused by inhibition of cell cycle progression from G₁ to S phase. At higher concentrations (500 µM for 24 h), morphine also caused cell death. In nude mice, morphine significantly reduced the growth of MCF-7 and MDA-MB231 tumors but had no effect on HT-29 tumor growth. In these experiments, morphine plasma concentrations were similar to those found in cancer patients receiving chronic morphine treatment for pain relief (0.9–3.4 µM). In MCF-7 and MDA-MB231 cells, morphine caused a naloxone (Nx)- and pertussis toxin-sensitive, concentration-dependent increase of GTPase activity, indicating that morphine signals could be transduced by opioid receptors via a G protein. However, the antiproliferative effects of morphine were not antagonized by Nx, pertussis toxin, forskolin, and 8-bromo-cAMP, suggesting that the typical opioid receptor-coupled signaling cascade involving the G_i, adenylyl cyclase, and protein kinase A was not involved. Instead, morphine caused an NH₂-terminal phosphorylation of p53 at Ser⁹ and/or Ser¹⁵ and a stabilization of p53 in MCF-7 cells that express wild-type p53. p53 phosphorylation was not antagonized by Nx and resulted in an increase of p53-dependent proteins including p21, Bax, and the death receptor Fas. Blockade of Fas by Fas-fusion protein or inhibition of caspase 8 resulted in a partial inhibition of morphine-induced apoptosis. In addition, Fas ligand only induced apoptosis when administered together with morphine. However, the sensitivity of the tumor cells toward Fas ligand remained low. HT-29 cells, which express dominant negative p53 and show no increase of GTPase activity when treated with morphine, were less sensitive in vitro and were not affected in vivo. Our results suggest that morphine, alone or in combination with Nx, may reduce the growth of certain tumors, apparently in part through activation of p53.

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