Department of Anatomy and Research Center for Tumor Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea.
Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
Int J Oncol. 2018 Feb;52(2):613-620. doi: 10.3892/ijo.2017.4227. Epub 2017 Dec 13.
Lung cancer is one of most common types of cancer worldwide. Lung cancer results in a death higher rate each year compared to colon, breast and prostate cancer combined. Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX‑2), an enzyme of which the expression is induced by various stimuli, such as inflammation. In addition, celecoxib triggers COX-2 loading on exosomes. Exosomes are small vesicles composed of a lipid bilayer membrane and are found in most biological fluids, such as blood breast milk and urine. In this study, we focused on exosomes containing COX-2 proteins from lung cancer cells to determine their involvement in the interaction with neighbor cells following treatment with celecoxib. We found that celecoxib induced COX-2 expression in both the cytosol and exosomes in lung cancer cells. Exosomes from celecoxib-treated lung cancer cell culture supernatant were isolated and incubated with several types of cells. The THP-1, monocytic leukemia cell line effectively absorbed COX-2 by lung cancer cell-derived exosomes. Following incubation with exosomes, the COX-2 protein level was increased in the THP-1 cells; however, COX-2 mRNA expression was not affected. Moreover, prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) production by THP-1 cells was increased following incubation with exosomes from celecoxib-treated lung cancer cells. Conditioned medium from THP-1 following incubation with exosomes promoted formation in EA.hy926 cells. Taken together, our findings suggest that celecoxib induces COX-2 expression in lung cancer cells, and that highly expressed COX-2 in exosomes can be transferred to other cells.
肺癌是全球最常见的癌症类型之一。与结肠癌、乳腺癌和前列腺癌加起来相比，肺癌每年导致的死亡率更高。塞来昔布是环氧化酶-2（COX-2）的选择性抑制剂，COX-2 是一种酶，其表达受各种刺激物（如炎症）诱导。此外，塞来昔布触发 COX-2 加载到外体上。外体是由脂质双层膜组成的小囊泡，存在于大多数生物液中，如血液、母乳和尿液。在这项研究中，我们专注于来自肺癌细胞的含有 COX-2 蛋白的外体，以确定它们在接受塞来昔布治疗后与相邻细胞相互作用中的参与情况。我们发现塞来昔布诱导肺癌细胞的细胞质和外体中的 COX-2 表达。从塞来昔布处理的肺癌细胞培养上清液中分离出外体，并与几种类型的细胞共孵育。THP-1，单核白血病细胞系有效地通过肺癌细胞衍生的外体吸收 COX-2。与外体共孵育后，THP-1 细胞中的 COX-2 蛋白水平增加，但 COX-2 mRNA 表达不受影响。此外，与来自塞来昔布处理的肺癌细胞的外体共孵育后，THP-1 细胞中前列腺素 E2（PGE2）和血管内皮生长因子（VEGF）的产生增加。与外体共孵育后的 THP-1 条件培养基促进 EA.hy926 细胞的形成。总之，我们的研究结果表明，塞来昔布诱导肺癌细胞中 COX-2 的表达，并且外体中高表达的 COX-2 可以转移到其他细胞。
