The novel role of the mu opioid receptor in lung cancer progression

A laboratory investigation

Biji Mathew, Frances E. Lennon, Jessica Siegler, Tamara Mirzapoiazova, Nurbek Mambetsariev, Saad Sammani, Lynnette M. Gerhold, Patrick J. Lariviere, Chin Tu Chen, Joe GN Garcia, Ravi Salgia, Jonathan Moss, Patrick A. Singleton

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

Background: The possibility that μ opioid agonists can influence cancer recurrence is a subject of recent interest. Epidemiologic studies suggested that there were differences in cancer recurrence in breast and prostate cancer contingent on anesthetic regimens. In this study, we identify a possible mechanism for these epidemiologic findings on the basis of μ opioid receptor (MOR) regulation of Lewis lung carcinoma (LLC) tumorigenicity in cell and animal models. Methods: We used human lung tissue and human non-small cell lung cancer (NSCLC) cell lines and evaluated MOR expression using immunoblot and immunohistochemical analysis. LLC cells were treated with the peripheral opioid antagonist methylnaltrexone (MNTX) or MOR shRNA and evaluated for proliferation, invasion, and soft agar colony formation in vitro and primary tumor growth and lung metastasis in C57BL/6 and MOR knockout mice using VisEn fluorescence mediated tomography imaging and immunohistochemical analysis. Results: We provide several lines of evidence that the MOR may be a potential target for lung cancer, a disease with high mortality and few treatment options. We first observed that there is ∼5-to 10-fold increase in MOR expression in lung samples from patients with NSCLC and in several human NSCLC cell lines. The MOR agonists morphine and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) increased in vitro LLC cell growth. Treatment with MNTX or silencing MOR expression inhibited LLC invasion and anchorage- independent growth by 50%-80%. Injection of MOR silenced LLC lead to a ∼65% reduction in mouse lung metastasis. In addition, MOR knockout mice do not develop significant tumors when injected with LLC in comparison with wild-type controls. Finally, continuous infusion of the peripheral opioid antagonist MNTX attenuates primary LLC tumor growth and reduces lung metastasis. Conclusions: Taken together, our data suggest a possible direct effect of opiates on lung cancer progression, and provide a plausible explanation for the epidemiologic findings. Our observations further suggest a possible therapeutic role for opioid antagonists.

Original languageEnglish (US)
Pages (from-to)558-567
Number of pages10
JournalAnesthesia and Analgesia
Volume112
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

Fingerprint

Lewis Lung Carcinoma
mu Opioid Receptor
Lung Neoplasms
Narcotic Antagonists
Lung
Non-Small Cell Lung Carcinoma
Neoplasms
Growth
Neoplasm Metastasis
Knockout Mice
Opiate Alkaloids
Recurrence
Cell Line
Enkephalins
Opioid Receptors
Morphine
Opioid Analgesics
Small Interfering RNA
Agar
Anesthetics

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Mathew, B., Lennon, F. E., Siegler, J., Mirzapoiazova, T., Mambetsariev, N., Sammani, S., ... Singleton, P. A. (2011). The novel role of the mu opioid receptor in lung cancer progression: A laboratory investigation. Anesthesia and Analgesia, 112(3), 558-567. https://doi.org/10.1213/ANE.0b013e31820568af

The novel role of the mu opioid receptor in lung cancer progression : A laboratory investigation. / Mathew, Biji; Lennon, Frances E.; Siegler, Jessica; Mirzapoiazova, Tamara; Mambetsariev, Nurbek; Sammani, Saad; Gerhold, Lynnette M.; Lariviere, Patrick J.; Chen, Chin Tu; Garcia, Joe GN; Salgia, Ravi; Moss, Jonathan; Singleton, Patrick A.

In: Anesthesia and Analgesia, Vol. 112, No. 3, 03.2011, p. 558-567.

Research output: Contribution to journalArticle

Mathew, B, Lennon, FE, Siegler, J, Mirzapoiazova, T, Mambetsariev, N, Sammani, S, Gerhold, LM, Lariviere, PJ, Chen, CT, Garcia, JGN, Salgia, R, Moss, J & Singleton, PA 2011, 'The novel role of the mu opioid receptor in lung cancer progression: A laboratory investigation', Anesthesia and Analgesia, vol. 112, no. 3, pp. 558-567. https://doi.org/10.1213/ANE.0b013e31820568af
Mathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani S et al. The novel role of the mu opioid receptor in lung cancer progression: A laboratory investigation. Anesthesia and Analgesia. 2011 Mar;112(3):558-567. https://doi.org/10.1213/ANE.0b013e31820568af
Mathew, Biji ; Lennon, Frances E. ; Siegler, Jessica ; Mirzapoiazova, Tamara ; Mambetsariev, Nurbek ; Sammani, Saad ; Gerhold, Lynnette M. ; Lariviere, Patrick J. ; Chen, Chin Tu ; Garcia, Joe GN ; Salgia, Ravi ; Moss, Jonathan ; Singleton, Patrick A. / The novel role of the mu opioid receptor in lung cancer progression : A laboratory investigation. In: Anesthesia and Analgesia. 2011 ; Vol. 112, No. 3. pp. 558-567.
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