Morphine Stimulates the Phosphorylation and Nuclear Translocation of EGFR in Lung Cancer Cells.

Mu opioid receptor (MOR) stimulates MAPK/ERK phosphorylation, by transactivating epidermal growth factor receptor (EGFR) in astrocytes (Belcheva MM et al J Biol Chem 2001, 276, 33847–53) and by transactivating vascular endothelial growth factor receptor-2 (VEGFR2) in endothelial cells (Chen C et al Curr Neurovasc Res 2006, 3, 171–80). EGFR and VEGFR2 are two critical targets for lung cancer therapy. Since opioids used to treat pain in cancer act via MOR, it is critical to understand the role of MOR in growth and survival promoting signaling in lung cancer. Therefore, we examined if MOR co-activates, EGFR mediated signaling in non-small cell human lung cancer cells, HL2009, HL1299 and HL460; and VEGFR2 in murine blood outgrowth endothelial cells (BOEC) derived from wild type (wt) and MOR knockout (KO) mice. We observed that HL2009 cells showed a 3–5 fold higher expression of MOR (by RT-PCR) as well as constitutive activation of phospho-EGFR (by Western) as compared to HL1299 and HL460. Morphine (100 nM) stimulated the phosphorylation of EGFR, MAPK/ERK and Akt in a time-dependent manner similar to that induced by 10 nM EGF, in HL2009 but not in HL460 cells. Morphine as well as EGF-induced phosphorylation peaked after 10 and 30 min of stimulation and it was accompanied by the translocation of phospho-EGFR to the nucleus in HL2009 but not in HL460 cells. Since, nuclear expression of phospho-EGFR is associated with poor prognosis in some human cancers, it is possible that MOR activation upon opioid exposure may impart resistance to lung cancer therapy, by stimulating the translocation of phospho-EGFR to the nucleus. On the other hand, morphine also stimulated the phosphorylation of VEGFR2 and MAPK/ERK in BOEC from wt mice but not in BOEC from MOR KO mice. Thus, opioid analgesics may stimulate VEGFR2 via MOR and stimulate angiogenesis. Acquired resistance to EGFR therapy in non small cell lung cancer is associated with increased VEGF activity. Therefore, simultaneous co-activation of EGFR and VEGFR2 via MOR in lung cancer may promote cancer progression and resistance to VEGF and/or EGFR based therapies. We speculate that MOR-specific antagonists in combination with VEGF/EGFR based therapies may prove to be beneficial in treating lung cancer.