Hypoxia increases CX3CR1 expression via HIF-1 and NF-κB in androgen-independent prostate cancer cells

• Published in: International journal of oncology Vol. 41; no. 5; pp. 1827 - 1836
• Main Authors: XIAO, LI-JIE, CHEN, YUAN-YUAN, LIN, PING, ZOU, HAI-FENG, LIN, FENG, ZHAO, LI-NAN, LI, DONG, GUO, LIANG, TANG, JIE-BING, ZHENG, XIU-LAN, YU, XIAO-GUANG
• Format: Journal Article
• Language: English
• Published: Athens D.A. Spandidos 01.11.2012; Editorial Academy of the International Journal of Oncology; Spandidos Publications UK Ltd
• Subjects: Androgens - metabolism; Biological and medical sciences; Cell Line, Tumor; Cell Movement - genetics; Chemokines; CX3C Chemokine Receptor 1; CX3CR1; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - metabolism; hypoxiainducible factor-1α; Male; Medical sciences; Metastasis; Neoplasm Metastasis; Nephrology. Urinary tract diseases; NF-kappa B - metabolism; nuclear factor-κB; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Receptors, Chemokine - genetics; Rodents; Studies; Transcription factors; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United States > US; CX3CR1; Oxygen; Urinary system disease; Prostate disease; Androgen; Malignant tumor; Metastasis; nuclear factor-κB; Cancerology; hypoxia-inducible factor-1α; Hormonoindependence; Hypoxia; Transcription factor HIF1; Transcription factor NFκB; Sex steroid hormone; Male genital diseases; Prostate cancer; Tumor cell; Cancer
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2012.1610

The unique CX3C chemokine CX3CL1 and its cognate receptor CX3CR1 have been implicated in organ-specific metastasis of various types of tumors. Hypoxia, a common phenomenon in solid tumors, is associated with a malignant cancer phenotype. Previous studies have proved that hypoxia facilitates cancer cell metastasis through upregulation of specific chemokine receptors. We hypothesized that hypoxia could upregulate CX3CR1 expression and lead to an increased chemotactic response to CX3CL1 in prostate cancer cells. In the present study, we found that CX3CR1 expression was significantly increased in androgen-independent prostate cancer cells, including DU145, PC-3 and PC-3M, following exposure to hypoxia. This upregulation of CX3CR1 corresponded to a significant increase in migration and invasion of prostate cancer cells under hypoxic conditions, which was attenuated after knocking down CX3CR1 expression. In addition, we examined the possible role of HIF-1 and NF-κB in the process of hypoxia-induced CX3CR1 expression and hypoxia-mediated metastasis. Attenuation of HIF-1 and NF-κB transcriptional activity by siRNAs or pharmacological inhibitors, abrogated hypoxia-induced upregulation of CX3CR1, and also prevented the migration and invasion of DU145 cells under a hypoxic environment. In summary, our study demonstrated that HIF-1 and NF-κB are essential for hypoxia-regulated CX3CR1 expression, which is associated with increased migratory and invasive potential of prostate cancer cells. CX3CR1 signaling is a potential therapeutic target in the adjuvant treatment of prostate cancer.