Abstract
BackgroundChronic 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.MethodsThe 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.ResultsIsoproterenol (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.ConclusionsThese 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.
Highlights
Chronic stress is well known to promote tumor progression, little is known whether chronic stress-mediated regulation of osteoblasts contributes to the migration and invasion of metastatic cancer cells
We demonstrated that β2-adrenergic receptor (β2AR)-Hypoxia inducible factor-1 alpha (HIF-1α)-Chemokine ligand 12 (CXCL12) of osteoblasts triggered by ISO contributed to migration and invasion of prostate cancer cells, which could be inhibited by the β2AR-blockers ICI118,551 and Chemokine receptor type 4 (CXCR4) inhibitor LY2510924
To obtain osteoblast-conditioned medium (OBCM), cells were grown to 90% confluence and culture media were changed to αMEM supplemented with 10% fetal bovine serum (FBS) with/without ISO
Summary
Chronic stress is well known to promote tumor progression, little is known whether chronic stress-mediated regulation of osteoblasts contributes to the migration and invasion of metastatic cancer cells. Emerging studies suggest that chronic psychological stress is a vital factor associated with poor clinical outcomes in cancer patients [2,3,4]. Β-blocker drugs that block β-adrenergic signaling may improve clinical outcomes of cancer patients [5, 6]. Isoproterenol (ISO), a nonselective β-adrenergic receptor (βAR) agonist as a pharmacological surrogate of sympathetic nerve activation, promoted invasion and metastasis of tumors both in vitro and in vivo [8,9,10]. Current studies demonstrated that central and sympathetic nervous systems activated by chronic stress contributed to the tumor metastasis through β2-adrenergic receptor (β2AR) [11]
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