1,2,3,4,6-Penta-O-galloly-beta-D-glucose suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1α and signaling in LNCaP prostate cancer cells.
Hypoxia is the hallmark of solid tumors and contributes to tumor angiogenesis mainly through activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). In addition to upregulating vascular endothelial growth factor (VEGF) in angiogenesis, HIF-1 plays critical roles in the metabolism, proliferation, metastasis, and differentiation of cancer cells. We and others have previously shown that 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) from Oriental herbal medicine possesses anti-angiogenic, anti-tumorigenic, and anti-diabetic activities. In the present study, we report that PGG inhibits hypoxia-induced protein accumulation, transcriptional activation, and mRNA expression of HIF-1α in LNCaP prostate cancer cells. PGG reduced cellular and secreted VEGF levels as well as mRNA expression in LNCaP cells. PGG suppressed capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxia-induced LNCaP cells, indicating that PGG has anti-angiogenic activity under hypoxic condition. Furthermore, PGG reduced expression of phosphoinositide 3-kinase (PI3K) as well as phosphorylation of AKT and mammalian target of rapamycin (mTOR), but not extracellular signal-regulated kinase (ERK) in LNCaP cells under hypoxic condition. Consistently, LY294002, a specific PI3K inhibitor, enhanced the inactivation of HIF-1α and AKT by PGG in LNCaP cells. Taken together, our results demonstrate that PGG inhibits hypoxia-mediated accumulation of HIF-1α as well as its downstream signaling to VEGF and PI3K/AKT/mTOR pathway in LNCaP prostate cancer cells.
College of Oriental Medicine, Kyung Hee University, Seoul 130–701, South Korea.
Ki-Young
KY
Park
Hyo-Jeong
HJ
Lee
Soo-Jin
SJ
Jeong
Hyo-Jung
HJ
Lee
Hyun-Seok
HS
Kim
Sun-Hyung
SH
Kim
Sabina
S
Lim
Ho-Cheol
HC
Kim
Junxuan
J
Lü
Sung-Hoon
SH
Kim
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D002196:Capillaries / Q000187:drug effects; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology* / Q000627:therapeutic use; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D047348:Hydrolyzable Tannins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010936:Plant Extracts; D042461:Vascular Endothelial Growth Factor A; C435084:pentagalloylglucose; D019870:1-Phosphatidylinositol 4-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases