title: Diosgenin targets Akt-mediated prosurvival signaling in human breast cancer cells.
abstract: In recent years, Akt signaling has gained recognition for its functional role in more aggressive, therapy-resistant malignancies. As it is frequently constitutively active in cancer cells, several drugs are being investigated for their ability to inhibit Akt signaling. The purpose of this study is to determine effect of diosgenin (fenugreek), a dietary compound on Akt signaling and its downstream targets on estrogen receptor positive (ER(+)) and estrogen receptor negative (ER(-)) breast cancer (BCa) cells. Diosgenin inhibits pAkt expression and Akt kinase activity without affecting PI3 kinase levels, resulting in the inhibition of its downstream targets, NF-kappaB, Bcl-2, survivin and XIAP. The Raf/MEK/ERK pathway, another functional downstream target of Akt, was inhibited by diosgenin in ER(+) but not in ER(-) BCa cells. Additionally, we found that diosgenin caused G1 cell cycle arrest by downregulating cyclin D1, cdk-2 and cdk-4 expression in both ER(+) and ER(-) BCa cells resulting in the inhibition of cell proliferation and induction of apoptosis. Interestingly, no significant toxicity was seen in the normal breast epithelial cells (MCF-10A) following treatment with diosgenin. Additionally, in vivo tumor studies indicate diosgenin significantly inhibits tumor growth in both MCF-7 and MDA-231 xenografts in nude mice. Thus, these results suggest that diosgenin might prove to be a potential chemotherapeutic agent for the treatment of BCa.
authors.affiliation: Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, KY 40536-0200, USA.
authors.forename: Sowmyalakshmi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Srinivas
authors.initials: S
authors.lastname: Koduru
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.forename: Guhan
authors.initials: G
authors.lastname: Venguswamy
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
authors.forename: Chendil
authors.initials: C
authors.lastname: Damodaran
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D004144:Diosgenin / Q000494:pharmacology*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D011960:Receptors, Estrogen; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D020169:Caspases; D004144:Diosgenin