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].
The hypoxia inducible factor-1 (HIF-1) is a transcription factor and also a key factor that maintains oxygen homeostasis in mammalian cells [
5]. HIF-1 is a heterodimer consisting of HIF-1α and β subunits [
6]. HIF-1α is dominantly expressed under hypoxic conditions, however, it exists in low levels under normoxic conditions [
7]. On the contrary, HIF-1β is expressed constitutively [
7]. In normoxic conditions, HIF-1α is hydroxylated by a tumour suppressor Von Hippel-Lindau (VHL) protein of the E3 ubiquitination ligase complex. Whereas, under hypoxic conditions, HIF-1α remains unhydroxylated and facilitates several factors, [
8‐
10] such as angiogenesis, tumour proliferation, tumour survival, and glycolysis [
11,
12]. Sphingosine-1-phoshate (S1P) is a signaling sphingolipid metabolite and a potent lipid mediator, which regulates progress in tumour cells such as cell growth, proliferation, apoptosis, invasion, angiogenesis, calcium homeostasis, and vascular maturation [
13,
14]. S1P precursors generate from sphingosine by sphingosine kinase 1 (SPHK-1), and the generation of S1P precursors triggers either a cell’s proliferation or death [
13]. SPHK-1 can act as a catalyst for the ATP-dependent phosphorylation of sphingosine, which stimulates a wide array of growth factors, such as PDGF, FGF, EGF, HGF, VEGF, etc. [
15‐
21]. 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].
Pristimerin is a naturally occurring triterpenoid quinone methide [
24,
25]. Several studies have demonstrated that pristimerin is involved in a variety of multiple biological activities related to anti-inflammatory, anti-oxidant, anti-cancer, anti-malarial, and anti-microbial action [
26‐
28]. Also, pristimerin has shown potent anti-cancer effects, including anti-proliferation, anti-migration, anti-angiogenesis, and apoptosis-inducing activity in various cancer cell lines, including glioma, leukemia, breast, lung, and prostate cancer cell lines [
24,
25,
29,
30] by inhibiting NF-kB [
29,
31‐
36]. Recently, Zuo, et al. reported that pristimerin has an inhibitory action on hypoxia-mediated metastasis [
4]. Nevertheless, the potential effects and the mechanism of pristimerin in hypoxia-mediated cancers still remain unknown.
Here, we demonstrate that pristimerin inhibits HIF-1α via the SPHK-1 signaling pathway in a prostate cancer cell lines. The results we have yielded provide the mechanism for inhibitory action of HIF-1α and angiogenesis by pristimerin in hypoxic prostate cancer cell lines.