Morphine-Induced Epidermal Growth Factor Pathway Activation in Non–Small Cell Lung Cancer

Abstract

Background Epidermal growth factor receptor (EGFR) is co-activated by the μ-opioid receptor (MOR), expressed on non-small cell lung cancer (NSCLC) cells and human lung cancer. We hypothesized that clinically used opioid analgesics that are MOR agonists co-activate EGFR, resulting in growth- and survival-promoting signaling. Methods We used H2009, a human adenocarcinoma NSCLC cell line, with constitutive EGFR phosphorylation, which showed increased expression of MOR and delta opioid receptor (DOR) by reverse transcriptase polymerase chain reaction. We used Western immunoblotting, magnetic bead-based Bio-plex cytokine assay, immunofluorescent staining, BrdU incorporation ELISA and BioCoat™ Matrigel™ invasion assay, to examine cell signaling, cytokine expression, co-localization of MOR and EGFR in human lung cancer, cell proliferation and invasion, respectively. Results Like epidermal growth factor (EGF), morphine stimulated phosphorylation of EGFR, Akt/protein kinase B (Akt), and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling in H2009 cells. Opioid receptor (OR) antagonist, naloxone, EGFR tyrosine kinase inhibitor, erlotinib, and silencing of MOR and DOR abrogated morphine- and EGF-induced phosphrylation of signaling, suggestive of OR mediated co-activation of EGFR. H2009 cells secreted significantly higher levels of cytokines as compared to control Beas2B epithelial cells. H2009 conditioned medium stimulated MOR expression in Beas2B cells, suggesting that cytokines secreted by H2009 may be associated with increased OR expression in H2009. We observed co-localization of EGFR and MOR, in human NSCLC tissue. Functionally, morphine and EGF-induced proliferation and invasion of H2009 cells was ameliorated by naloxone as well as erlotinib. Conclusion Morphine-induced phosphorylation of EGFR occurs via ORs, leading to downstream MAPK/ERK, Akt phosphorylation, cell proliferation and increased invasion. Notably, ORs are also associated with EGF-induced phosphorylation of EGFR. Increased co-expression of MOR and EGFR in human lung cancer suggests that morphine may have a growth-promoting effect in lung cancer.

Can anesthetic-analgesic technique during primary cancer surgery affect recurrence or metastasis?

“…47 Several studies have focused on the actions of the lopioid receptor (MOR) in the regulation of tumour growth and metastasis. 48,49 The overexpression of MOR has been shown in both lung 50,51 and prostate cancer. 52 The theory regarding MOR involvement in metastasis is further supported by the diminished progression of lung carcinoma in MOR knockout mice treated with the opioid receptor antagonist naltrexone.…”

Exogenous Morphine Inhibits Human Gastric Cancer MGC-803 Cell Growth by Cell Cycle Arrest and Apoptosis Induction

“…Pre-clinical observations are complemented by a series of clinical studies demonstrating that both pre-and post-operative administration of analgesic dosages of morphine as an adjuvant to cancer surgery operationally reduces systemic cell dissemination of tumor cells (Page et al, 1994;. However, morphine is also suggested to promote the development of cancer because several researches demonstrated that morphine enhanced the growth of several different tumor cell lines in vivo (Ishikawa et al, 1993;Fujioka et al, 2011).…”

Could Perioperative Opioid Use Increase the Risk of Cancer Progression and Metastases?

“…21 Opioid-induced cell proliferation, growth and migration have been observed in different cell types. 6,8,9,12,22–26 In human lung, prostate and colon cancer tissues, high expression of MOP-R has been observed as compared to healthy tissue. 9,18,27–29 We and others demonstrated that MOP-R expression is associated with tumor progression (but not tumor initiation) in lung 9,12 and breast cancer 6 in mice.…”

“…6,8,9,12,22–26 In human lung, prostate and colon cancer tissues, high expression of MOP-R has been observed as compared to healthy tissue. 9,18,27–29 We and others demonstrated that MOP-R expression is associated with tumor progression (but not tumor initiation) in lung 9,12 and breast cancer 6 in mice. Additionally, in a retrospective clinical study of patients with advanced prostate cancer receiving androgen deprivation therapy, we found that greater opioid requirement or higher levels of MOP-R expression in the tumor are independently associated with shorter progression-free survival and overall survival (Table 1).…”