Abstract
BackgroundHypoxia is a typical character of locally advanced solid tumours. The transcription factor hypoxia-inducible factor 1α (HIF-1α) is the main regulator under the hypoxic environment. HIF-1α regulates various genes to enhance tumour progression, angiogenesis, and metastasis. Sphingosine kinase 1 (SPHK-1) is a modulator of HIF-1α.MethodsTo 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.ResultsPristimerin inhibited HIF-1α accumulation in a concentration- and-time-dependent manner in hypoxic PC-3 cells. Pristimerin suppressed the expression of HIF-1α by inhibiting SPHK-1. Moreover, inhibiting SPHK-1 with a sphingosine kinase inhibitor enhanced the suppression of HIF-1α, phosphorylation AKT, and glycogen synthase kinase-3β (GSK-3β) by pristimerin under hypoxia. Furthermore, a reactive oxygen species (ROS) scavenger enhanced the inhibition of HIF-1α and SPHK-1 by pristimerin.ConclusionTaken together, these findings suggest that pristimerin can exert an anti-cancer activity by inhibiting HIF-1α through the SPHK-1 pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2730-2) contains supplementary material, which is available to authorized users.
Highlights
Hypoxia is a typical character of locally advanced solid tumours
Pristimerin decreases hypoxiainducible factor 1α (HIF-1α) abundance and Vascular endothelial growth factor (VEGF) secretion To examine whether pristimerin inhibits hypoxiainduced HIF-1α, pristimerin was treated into PC-3 cells under hypoxia for 4 h
reactive oxygen species (ROS) mediates pristimerin inhibited Sphingosine kinase 1 (SPHK-1) and HIF-1α in hypoxic PC-3 cells To examine whether ROS mediate pristimerin-induced inhibition of HIF-1α and SPHK-1, PC-3 cells were treated with pristimerin or/and NAC
Summary
Hypoxia is a typical character of locally advanced solid tumours. The transcription factor hypoxiainducible factor 1α (HIF-1α) is the main regulator under the hypoxic environment. Hypoxia is a common characteristic of locally advanced solid tumours [1] and up to 50–60 % of solid tumours include areas of hypoxic tissues [2]. The hypoxic tumour contributes to aggressive and metastatic cancer phenotypes that are associated with resistance to radiation therapy, chemotherapy, and a poor treatment outcome [3, 4]. SPHK-1 mRNA is overexpressed in various solid tumours, such as a breast, brain, lung, stomach, colon, kidney, and ovary tumours [22]. Several studies have demonstrated that SPHK-1 controls the level of HIF-1α during hypoxia in cancer cells [23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
