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Morphine Suppresses Lung Cancer Cell Proliferation Through the Interaction with Opioid Growth Factor Receptor: An In Vitro and Human Lung Tissue Study

Kim, Ji Yeon MD, PhD; Ahn, Hyun Joo MD, PhD; Kim, Jin Kyoung MD, PhD; Kim, Jhingook MD, PhD; Lee, Sang Hyun MD; Chae, Hyun Byung MD

doi: 10.1213/ANE.0000000000001293
Preclinical Pharmacology: Original Laboratory Research Report

BACKGROUND: There have been inconsistent reports on whether opioids promote or inhibit lung cancer growth. In this study, we suggest that opioid growth factor receptor (OGFR), a negative regulator of cell proliferation, is a binding site of morphine and is involved in subsequent morphine-induced lung cancer growth suppression.

METHODS: The expression and distribution of OGFR in human lung cancer tissues and cell lines were assessed with immunohistochemistry and real-time reverse transcription polymerase chain reaction. The human lung cancer cell line, H1975 (adenocarcinoma), which overexpressed OGFR but not μ-opioid receptors, was selected for further analysis to verify the interaction between morphine and OGFR and the impact of morphine on cancer cell growth.

RESULTS: OGFR was expressed in lung cancer tissues and all cancer cell lines tested. Adenocarcinoma showed a higher OGFR expression than squamous cell carcinoma (reverse transcription polymerase chain reaction relative quantitation value: median [interquartile range], 13.1 [9.3–20.0] vs 4.3 [2.2–6.6]; P = 0.003). OGFR expression showed an inverse correlation with cell proliferation (r = −0.92, P = 0.0001). Morphine treatment reduced the median H1975 cell number by approximately 23% (P = 0.03). Growth suppression by morphine was attenuated when OGFR was knocked down. A confocal experiment demonstrated binding of morphine to OGFR. Growth suppression by morphine occurred in the S phase of the cell cycle.

CONCLUSIONS: Lung cancer tissues and cell lines express OGFR. Morphine interacts with OGFR and may suppress lung cancer progression.

Published ahead of print May 10, 2016.

From the *Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; and Department of Thoracic and Cardiovascular surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Published ahead of print May 10, 2016.

Accepted for publication January 28, 2016.

Funding: This project was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology award number 2011-0013087. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Hyun Joo Ahn, MD, PhD, Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Gu, Seoul, Korea, 135–710. Address e-mail to hyunjooahn@skku.edu.

© 2016 International Anesthesia Research Society