Abstract
Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor (MOR) can influence cancer progression. Based on our previous observations that overexpression of MOR in human non-small cell lung cancer (NSCLC) cells increased tumor growth and metastasis, this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition (EMT) in human NSCLC cells. We utilized specific siRNA, shRNA, chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO, morphine, fentanyl, EGF or IGF. Cell function assays, immunoblot and immunoprecipitation assays were then performed. Our results indicate MOR regulates opioid and growth factor-induced EGF receptor signaling (Src, Gab-1, PI3K, Akt and STAT3 activation) which is crucial for consequent human NSCLC cell proliferation and migration. In addition, human NSCLC cells treated with opioids, growth factors or MOR overexpression exhibited an increase in snail, slug and vimentin and decrease ZO-1 and claudin-1 protein levels, results consistent with an EMT phenotype. Further, these effects were reversed with silencing (shRNA) or chemical inhibition of MOR, Src, Gab-1, PI3K, Akt and STAT3 (p<0.05). Our data suggest a possible direct effect of MOR on opioid and growth factor-signaling and consequent proliferation, migration and EMT transition during lung cancer progression. Such an effect provides a plausible explanation for the epidemiologic findings.
Highlights
The role of anesthesia and analgesia in the recurrence and metastatic rate of malignancies has recently received considerable attention [1,2,3,4]
Based on the recent interest of the effects of anesthesia and analgesia regimens on the recurrence and metastatic potential of various cancers [1,2,3,4], our previous published data indicating the mu opioid receptor (MOR) is upregulated in lung tissue from patients with non-small cell lung cancer (NSCLC) [12], overexpression of MOR promotes tumor growth and metastasis in human NSCLC xenograft models [13] as well as data from Fujioka et al, demonstrating MOR regulation of EGFinduced signaling events in NSCLC [35], this study investigated the functional effects of MOR in the fundamental oncogenic processes of opioid and growth factor-induced human lung cell migration, proliferation and epithelial mesenchymal transition (EMT)[16,17,18,19,20]
Based on our results that a MOR/epidermal growth factor receptor (EGFR) complex can occur with EGF stimulation of H358 cells, we examined whether MOR can regulate EGFR phosphorylation
Summary
The role of anesthesia and analgesia in the recurrence and metastatic rate of malignancies has recently received considerable attention [1,2,3,4]. For cancer cells to grow and metastasize, there needs to be a loss of cell-cell adhesion (characterized by a reduction of epithelial cell adhesion proteins including the tight junction proteins, ZO-1 and claudin-1) followed by acquisition of mesenchymal characteristics including a loss of baso-apical polarization, cytoskeletal remodeling and increased cell motility (characterized by increases in specific cytoskeletal proteins (i.e. vimentin) and transcription factors (i.e. Slug and Snail) [16,17,18,19] This orchestrated oncogenic process is referred to as epithelial mesenchymal transition (EMT) [16,17,18,19,20,21,22]
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