title: AMR-Me inhibits PI3K/Akt signaling in hormone-dependent MCF-7 breast cancer cells and inactivates NF-κB in hormone-independent MDA-MB-231 cells.
abstract: AMR-Me, a C-28 methylester derivative of triterpenoid compound Amooranin isolated from Amoora rohituka stem bark and the plant has been reported to possess multitude of medicinal properties. Our previous studies have shown that AMR-Me can induce apoptosis through mitochondrial apoptotic and MAPK signaling pathways by regulating the expression of apoptosis related genes in human breast cancer MCF-7 cells. However, the molecular mechanism of AMR-Me induced apoptotic cell death remains unclear. Our results showed that AMR-Me dose-dependently inhibited the proliferation of MCF-7 and MDA-MB-231 cells under serum-free conditions supplemented with 1 nM estrogen (E2) with an IC50 value of 0.15 µM, 0.45 µM, respectively. AMR-Me had minimal effects on human normal breast epithelial MCF-10A + ras and MCF-10A cells with IC50 value of 6 and 6.5 µM, respectively. AMR-Me downregulated PI3K p85, Akt1, and p-Akt in an ERα-independent manner in MCF-7 cells and no change in expression levels of PI3K p85 and Akt were observed in MDA-MB-231 cells treated under similar conditions. The PI3K inhibitor LY294002 suppressed Akt activation similar to AMR-Me and potentiated AMR-Me induced apoptosis in MCF-7 cells. EMSA revealed that AMR-Me inhibited nuclear factor-kappaB (NF-κB) DNA binding activity in MDA-MB-231 cells in a time-dependent manner and abrogated EGF induced NF-κB activation. From these studies we conclude that AMR-Me decreased ERα expression and effectively inhibited Akt phosphorylation in MCF-7 cells and inactivate constitutive nuclear NF-κB and its regulated proteins in MDA-MB-231 cells. Due to this multifactorial effect in hormone-dependent and independent breast cancer cells AMR-Me deserves attention for use in breast cancer prevention and therapy.
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland; K.R. Sterling Cancer and Aids Hospital, Chennai, Tamilnadu, India.
authors.forename: Thangaiyan
authors.initials: T
authors.lastname: Rabi
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
authors.forename: Uwe
authors.initials: U
authors.lastname: Zangemeister-Wittke
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D017232:Oncogene Proteins v-mos / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors*; D051841:Transcription Factor RelB / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004967:Estrogens; D009025:Morpholines; D016328:NF-kappa B; D009687:Nuclear Proteins; D009828:Oleanolic Acid; D017232:Oncogene Proteins v-mos; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; C068059:REL protein, human; C498143:RELA protein, human; C497593:RELB protein, human; C530744:methyl 25-hydroxy-3-oxoolean-12-en-28-oate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: AMR-Me; ER; NF-κB; PI3K/Akt; breast cancer cells