title: Marine lipopeptide Iturin A inhibits Akt mediated GSK3β and FoxO3a signaling and triggers apoptosis in breast cancer.
abstract: Akt kinase is a critical component of the PI3K/Akt signaling pathway, which is frequently over expressed in human cancers including breast. Therapeutic regimens for inhibiting breast cancer with aberrant Akt activity are essential. Here, we evaluated antitumor effect of a marine bacteria derived lipopeptide 'Iturin A' on human breast cancer in vitro and in vivo through disrupting Akt pathway. Proliferation of MDA-MB-231 and MCF-7 breast cancer cells were significantly inhibited by Iturin A and it induced apoptosis as confirmed by increased Sub G1 populations, DNA fragmentation, morphological changes and western blot analysis. Furthermore, Iturin A inhibited EGF induced Akt phosphorylation (Ser473 and Thr308) and its downstream targets GSK3β and FoxO3a. Iturin A inactivated MAPK as well as Akt kinase leading to the translocation of FoxO3a to the nucleus. Gene silencing of Akt in MDA-MB-231 and MCF-7 cells reduced the sensitivity of cancer cells to Iturin A. Interestingly, overexpression of Akt with Akt plasmid in cancer cells caused highly susceptible to induce apoptosis by Iturin A treatment. In a xenograft model, Iturin A inhibited tumor growth with reduced expressions of Ki-67, CD-31, P-Akt, P-GSK3β, P-FoxO3a and P-MAPK. Collectively, these findings imply that Iturin A has potential anticancer effect on breast cancer.
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: Goutam
authors.initials: G
authors.lastname: Dey
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bharti
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: Gunaseelan
authors.initials: G
authors.lastname: Dhanarajan
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: Subhasis
authors.initials: S
authors.lastname: Das
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: Kaushik Kumar
authors.initials: KK
authors.lastname: Dey
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: B N Prashanth
authors.initials: BN
authors.lastname: Kumar
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: Ramkrishna
authors.initials: R
authors.lastname: Sen
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
authors.forename: Mahitosh
authors.initials: M
authors.lastname: Mandal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001410:Bacillus megaterium / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010456:Peptides, Cyclic; C013579:iturin A; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3