Penta-1,2,3,4,6-O-galloyl-β-d-glucose induces p53 and inhibits STAT3 in prostate cancer cellsin vitroand suppresses prostate xenograft tumor growthin vivo

Abstract

Penta-1,2,3,4,6-O-galloyl-B-D-glucose (PGG) is a naturally occurring gallotannin from some Oriental herbs. Several cell culture studies suggested a potential for PGG as a novel agent for the chemoprevention and treatment of cancer. Here, we investigated the cell death signaling mechanisms induced by PGG in human prostate cancer cells of different p53 functional status. We observed the induction of G 1 -and S-phase arrests and caspasemediated apoptosis in the androgen-dependent human LNCaP cells, which express wild-type p53, and in the androgen-independent, p53-mutant DU145 cells. In LNCaP cells, caspase-mediated apoptosis induction by PGG was associated with and mediated in major part by activation of p53 as established through small interfering RNA knockdown and dominant-negative mutant approaches. Intracellular reactive oxygen species production by PGG was found to be crucial for these molecular and cellular actions. In DU145 cells, which harbor constitutively active signal transducer and activator of transcription 3 (STAT3), caspase-mediated apoptosis induction by PGG was associated with an inhibition of STAT3 Tyr 705 phosphorylation and the down-regulation of STAT3 transcriptional targets Bcl-XL and Mcl-1. Overexpression of Bcl-XL or knockdown of its binding partner Bak attenuated apoptosis induction. Furthermore, we provide, for the first time, in vivo data that PGG significantly inhibited DU145 xenograft growth in an athymic nude mouse model in association with an inhibition of pSTAT3. Our data support PGG as a multitargeting agent for chemoprevention and therapy of prostate cancer by activating the p53 tumor suppressor pathway and by inhibiting STAT3 oncogenic signaling.

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

“…10,32) PGG isolated from medicinal herbs has been previously studied for its anti-tumorigenic, anti-angiogenenic, and antidiabetic activities. [15][16][17][18][33][34][35] In the current study, we investigated whether PGG can inhibit hypoxia-mediated HIF-1a activation in LNCaP prostate cancer cells. First of all, our data confirm that hypoxia significantly enhanced the expression of HIF-1a at protein level, consistent with previous evidence in LNCaP cells.…”

“…16) To evaluate whether hypoxia can influence the acute cytotoxicity of PGG against LNCaP prostate cancer cells, we performed XTT assay to check the metabolic viability after 6-h exposure. As shown in Fig.…”

“…1B), which is consistent with our previous studies. 16) PGG Inhibits Hypoxia-Induced HIF-1a Protein Accumulation in LNCaP Cells HIF-1a induction is an important response to hypoxia. 21) Consistent with this, hypoxia induced in 1% O 2 chamber significantly increased protein expression of HIF-1a in a time-dependent manner (peak time was 6 h), whereas normoxia had no effect on HIF-1a protein level in LNCaP cells (Fig.…”

“…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.…”

Penta-O-galloyl-beta-D-glucose enhances antitumor activity of imatinib and suppresses the growth of K562 cells in mice

“…Also, it is of note that PGG exerts antitumor activity in various cancers such as prostate (Hu et al, 2008), lung (Huh et al, 2005), breast (Chen et al, 2003), melanoma (Ho et al, 2002), liver cancers (Oh et al, 2001) and sarcomas (Miyamoto et al, 1987). Nevertheless, there are no evidences regarding the synergistic antitumor effect of PGG with imatinib so far.…”