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

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

  • BMC Cancer. 2019 Nov 26;19(1):1142. doi: 10.1186/s12885-019-6301-1.
Zhibin Huang 1 2 3 Guihuan Li 2 Zhishuai Zhang 2 Ruonan Gu 1 2 Wenyang Wang 2 Xiaoju Lai 2 Zhong-Kai Cui 2 Fangyin Zeng 4 Shiyuan Xu 5 Fan Deng 6
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
  • 2 Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Anesthesiology, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, 350001, China.
  • 4 Department of Clinical Laboratory, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510900, China. zengfy@126.com.
  • 5 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. xsy998@smu.edu.cn.
  • 6 Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. fandeng@smu.edu.cn.
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Bone metastasis; Cancer; Chronic stress; Sympathetic nerve.

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