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
  • 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. [email protected].
  • 5. Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. [email protected].
  • 6. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. [email protected].
PMID: 31771535 DOI: 10.1186/s12885-019-6301-1
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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