title: Insulin receptor signaling activated by penta-O-galloyl-α-D: -glucopyranose induces p53 and apoptosis in cancer cells.
abstract: p53 is essential for cell cycle arrest and apoptosis induction while insulin receptor (IR) signaling is important for cell metabolism and proliferation and found upregulated in cancers. While IR has recently been found to be involved in apoptosis, p53 induction or apoptosis mediated through IR signaling activation has never been documented. Here, we report that the IR signaling pathway, particularly the IR-MEK pathway, mediates biological and biochemical changes in p53 and apoptosis in tumor cells. Specifically, natural compound penta-O-galloyl-α-D: -glucopyranose (α-PGG), a previously characterized IR signaling activator, induced apoptosis in RKO cells without significantly affecting its normal counterpart FHC cells. α-PGG induced apoptosis in RKO cells through p53, Bax and caspase 3. Importantly, α-PGG's ability to elevate p53 was diminished by IR inhibitor and IR-siRNA, suggesting a non-conventional role of IR as being involved in p53 induction. Further studies revealed that α-PGG activated MEK, a downstream signaling factor of IR. Blocking MEK significantly suppressed α-PGG-induced p53 and Bax elevation. All these results suggested that α-PGG induced p53, Bax, and apoptosis through the IR-MEK signaling pathway. The unique activity of α-PGG, a novel IR phosphorylation and apoptosis inducer, may offer a new therapeutic strategy for eliciting apoptotic signal and inhibiting cancer growth.
authors.affiliation: Department of Biological Sciences, Ohio University, Athens, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cao
authors.forename: Susan C
authors.initials: SC
authors.lastname: Evans
authors.forename: Eroica
authors.initials: E
authors.lastname: Soans
authors.forename: Ahmed
authors.initials: A
authors.lastname: Malki
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaozhuo
authors.initials: X
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000187:drug effects; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D047348:Hydrolyzable Tannins; D009281:Naphthalenes; D063065:Organophosphonates; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C519736:hydroxy-2-naphthalenyl-methyl phosphonic acid trisacetoxymethylester; C435084:pentagalloylglucose; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3