1,2,3,4,6-Penta-O-galloly-beta-D-glucose Suppresses Hypoxia-Induced Accumulation of Hypoxia-Inducible Factor-1.ALPHA. and Signaling in LNCaP Prostate Cancer Cells

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a role in cell survival in response to hypoxia and is overexpressed in many human solid cancers. HIF-1 consists of two subunits, HIF-1a and HIF1b.1) HIF-1a is steadily degraded by the ubiquitin-proteasome pathway under normoxic condition and stabilized under hypoxic condition, in contrast to HIF-1b, which is constitutively expressed. In the presence of iron and oxygen, HIF-1a is hydroxylated by prolyl hydroxylase domain (PHD) on residues 402 and 564, which are in the oxygendependent degradation (ODD) region. 2,3)HIF-1a plays important roles in the promotion of cancer angiogenesis, cell proliferation, and erythropoiesis. [4][5][6] HIF1a activates transcription of the promoter of vascular endothelial growth factor (VEGF), a key factor in tumor angiogenesis. 7) Angiogenesis is the process involving the growth of new blood vessels from pre-existing vessels 8) and is crucial for tumor growth and metastasis. 9) Thus, HIF-1a/VEGF system has been considered a promising target for antiangiogenic and anti-cancer therapy. 10)In addition, HIF-1a has been linked to the oncogenic phosphoinositide 3-kinase (PI3K)/AKT signaling pathway in many types of cancer.11,12) Accumulation of HIF-1a protein also depends on the AKT/mammalian target of rapamycin (mTOR) pathway. 13)Recently, many anti-tumor herbal drugs and natural compounds have become very attractive due to little side effects at nontoxic concentrations. We and others have reported that 1,2,3,4,6-penta-O-galloyl-b-D-glucose (PGG), a naturally occurring gallotannin polyphenolic compound highly enriched in a number of medicinal herbals such as Rhus chinensis MILL and Paeonia suffruticos, possesses potent anti-angiogenic activity in a battery of in vitro angiogenesis tests using human umbilical vein endothelial cell (HUVEC) and in vivo angiogenesis and Lewis lung carcinoma (LLC) allograft models.14,15) Our collaborative team and others have recently demonstrated the in vivo efficacy of PGG against prostate xenograft models. 16,17) PGG also has been shown to exert various biological activities such as anti-cancer, anti-angiogenic, anti-diabetic, and anti-oxidation effects. 14,18,19) While the anti-angiogenic activity of PGG has been implicated as a contributor to tumor growth suppression, no studies have examined the direct impact of PGG on HIF-1a accumulation and angiogenic signaling pathway in prostate cancer cells.In the present study, we demonstrate the effects of PGG on hypoxia-induced protein accumulation, transcriptional activation of HIF-1a, and PI3K/AKT/mTOR pathway in LNCaP prostate cancer cells. MATERIALS AND METHODSIsolation of PGG Isolation of PGG (molecular weight (MW)ϭ940) from the gallnut of R. chinensis has been described previously. 15)Cell Culture and Hypoxia Induction LNCaP human prostate cancer cells were obtained from the Korea Cell Line Bank (KCLB) (Seoul, South Korea) and maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 0.45% D-glucose, 10...

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

“…The VEGF production level measurement methods was previously described in our other study [39]. The culture supernatants was added in a 96-well plate, and reacted with dilution buffer and incubation buffer at room temperature for 2 h. The wells were then washed four times with washing buffer, and then biotin conjugate was added to each well at room temperature for 1 h. After washing, the stabilized chromogen was added into each well and reacted for 30 min at room temperature.…”

Cofilin-1 is involved in regulation of actin reorganization during influenza A virus assembly and budding

“…It has been reported that PGG reduces the expression of PI3K as well as phosphorylation of AKT and mammalian target of rapamycin (mTOR) [39]. It is likely that PGG suppress IAV-induced cofilin-1 phosphorylation via inhibition of the PI3K/Akt pathway.…”

Downregulation of signalling molecules involved in angiogenesis of prostate cancer cell line (PC-3) by kombucha (lyophilized)

“…Tumour hypoxia is caused by an imbalance between cellular O 2 use and supply rates in the cells via activation of the transcription factor HIF-1␣. HIF-1␣ is over expressed in many types of cancers and plays an important role in angiogenesis by regulating VEGF expression [5]. HIF-1␣ activates transcription of the promoter of vascular endothelial growth factor (VEGF), a key factor in tumour angiogenesis.…”

“…It deactivates transcription of the promoter of VEGF. Hypoxia-inducible factor-1 is a heterodimeric transcription factor that plays a role in cell survival in response to hypoxia and is over expressed in many human solid cancers [5].…”

“…HIF-1␣ is steadily degraded by the ubiquitin-proteasome pathway under normoxic condition and stabilized under hypoxic condition. HIF-1␣ plays important roles in the promotion of cancer angiogenesis, cell proliferation, and erythropoiesis [5]. HIF-1␣ activates transcription of the promoter of vascular endothelial growth factor (VEGF), a key factor in tumour angiogenesis.…”