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

Ki Young Park, Hyo Jeong Lee, Soo Jin Jeong, Hyo Jung Lee, Hyun Seok Kim, Sun Hyung Kim, Sabina Lim, Ho Cheol Kim, Junxuan Lü, Sung Hoon Kim

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Abstract

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-1 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-1 and AKT by PGG in LNCaP cells. Taken together, our results demonstrate that PGG inhibits hypoxia-mediated accumulation of HIF-1 as well as its downstream signaling to VEGF and PI3K/AKT/mTOR pathway in LNCaP prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)1835-1840
Number of pages6
JournalBiological and Pharmaceutical Bulletin
Volume33
Issue number11
DOIs
StatePublished - Nov 19 2010

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All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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