Penta-1,2,3,4,6-O-galloyl-beta-D-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitro and suppresses prostate xenograft tumor growth in vivo.
Penta-1,2,3,4,6-O-galloyl-beta-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 caspase-mediated 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 Tyr705 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.
Hu
Hongbo
H
The Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912, USA.
Lee
Hyo-Jeong
HJ
Jiang
Cheng
C
Zhang
Jinhui
J
Wang
Lei
L
Zhao
Yan
Y
Xiang
Qiu
Q
Lee
Eun-Ok
EO
Kim
Sung-Hoon
SH
Lü
Junxuan
J
D000728:Androgens / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002474:Cell-Free System; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047348:Hydrolyzable Tannins / Q000737:chemistry / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016196:S Phase / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000728:Androgens; D000970:Antineoplastic Agents; D047348:Hydrolyzable Tannins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C435084:pentagalloylglucose; D006861:Hydrogen Peroxide; D020169:Caspases