Anti-cancer effect of pristimerin by inhibition of HIF-1 alpha involves the SPHK-1 pathway in hypoxic prostate cancer cells

作者：Lee Seon Ok; Kim Joo Seok; Lee Myoung Sun; Lee Hyo Jeong^*

来源：BMC Cancer, 2016, 16(1): 701.

DOI：10.1186/s12885-016-2730-2

• Hypoxia
• Pristimerin
• SPHK-1
• Prostate cancer
• HIF-1 alpha

Background: Hypoxia is a typical character of locally advanced solid tumours. The transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha) is the main regulator under the hypoxic environment. HIF-1 alpha regulates various genes to enhance tumour progression, angiogenesis, and metastasis. Sphingosine kinase 1 (SPHK-1) is a modulator of HIF-1 alpha.
Methods: To investigate the molecular mechanisms of pristimerin in association with SPHK-1 pathways in hypoxic PC-3 cancer cells. Vascular endothelial growth factor (VEGF) production, cell cycles, and SPHK-1 activity were measured, and western blotting, an MTT assay, and an RNA interference assay were performed.
Results: Pristimerin inhibited HIF-1 alpha accumulation in a concentration- and-time-dependent manner in hypoxic PC-3 cells. Pristimerin suppressed the expression of HIF-1 alpha by inhibiting SPHK-1. Moreover, inhibiting SPHK-1 with a sphingosine kinase inhibitor enhanced the suppression of HIF-1 alpha, phosphorylation AKT, and glycogen synthase kinase-3 beta (GSK-3 beta) by pristimerin under hypoxia. Furthermore, a reactive oxygen species (ROS) scavenger enhanced the inhibition of HIF-1 alpha and SPHK-1 by pristimerin.
Conclusion: Taken together, these findings suggest that pristimerin can exert an anti-cancer activity by inhibiting HIF-1 alpha through the SPHK-1 pathway.

• 出版日期2016-8-31