β2AR-HIF-1α-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells

• Published in: BMC cancer 2019-11, Vol.19 (1), p.1142-1142, Article 1142
• Main Authors: Huang, Zhibin, Li, Guihuan, Zhang, Zhishuai, Gu, Ruonan, Wang, Wenyang, Lai, Xiaoju, Cui, Zhong-Kai, Zeng, Fangyin, Xu, Shiyuan, Deng, Fan
• Format: Article
• Language: English
• Subjects: Animals; Bone cancer; Bone marrow; Bone metastasis; Cancer; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Chemokine CXCL12 - metabolism; Chemokines; Cholecystokinin; Chronic stress; Clinical outcomes; Culture Media, Conditioned - pharmacology; CXCL12 protein; CXCR4 protein; Cytokines; Epithelial-Mesenchymal Transition - drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Isoproterenol; Isoproterenol - pharmacology; Laboratory animals; Ligands; Male; Medical research; Membranes; Mesenchyme; Metastases; Metastasis; Mice; mRNA; Osteoblasts; Osteoblasts - drug effects; Osteoblasts - metabolism; Polyclonal antibodies; Prostate cancer; Prostatic Neoplasms - metabolism; Proteins; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction - drug effects; siRNA; Sympathetic nerve; Sympathetic nerves; Transfection; Tumors
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-019-6301-1

Chronic stress is well known to promote tumor progression, however, little is known whether chronic stress-mediated regulation of osteoblasts contributes to the migration and invasion of metastatic cancer cells. The proliferation, migration and invasion of prostate cancer cells were assessed by CCK-8 and transwell assay. HIF-1α expression of osteoblasts and epithelial-mesenchymal transition (EMT) markers of prostate cancer cells were examined by Western blot. The mRNA level of cytokines associated with bone metastasis in osteoblasts and EMT markers in PC-3 and DU145 cells were performed by qRT-PCR. Functional rescue experiment of cells were performed by using siRNA, plasmid transfection and inhibitor treatment. Isoproterenol (ISO), a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibited no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promoted EMT, migration and invasion of PC-3 and DU145 cells, which could be inhibited by β2AR inhibitor. Mechanistically, ISO increased the secretion of CXCL12 via the β2AR-HIF-1α signaling in osteoblasts. Moreover, overexpression of HIF-1α osteoblasts promoted migration and invasion of PC-3 and DU145 cells, which was inhibited by addition of recombinant knockdown of CXCR4 in PC-3 and DU145 cells, and inhibiting CXCL12-CXCR4 signaling with LY2510924 blunted the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. These findings demonstrated that β2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer.