Therapeutic implication of 'Iturin A' for targeting MD-2/TLR4 complex to overcome angiogenesis and invasion.

Abstract

Tumor angiogenesis and invasion are deregulated biological processes that drive multistage transformation of tumors from a benign to a life-threatening malignant state activating multiple signaling pathways including MD-2/TLR4/NF-κB. Development of potential inhibitors of this signaling is emerging area for discovery of novel cancer therapeutics. In the current investigation, we identified Iturin A (A lipopeptide molecule from Bacillus megaterium) as a potent inhibitor of angiogenesis and cancer invasion by various in vitro and in vivo methods. Iturin A was found to suppress VEGF, a powerful inducer of angiogenesis and key player in tumor invasion, as confirmed by ELISA, western blot and real time PCR. Iturin A inhibited endothelial tube arrangement, blood capillary formation, endothelial sprouting and vascular growth inside the matrigel. In addition, Iturin A inhibited MMP-2/9 expression in MDA-MB-231 and HUVEC cells. Cancer invasion, migration and colony forming ability were significantly hampered by Iturin A. Expressions of MD-2/TLR4 and its downstream MyD88, IKK-α and NF-κB were also reduced in treated MDA-MB-231 and HUVEC cells. Western blot and immunofluorescence study showed that nuclear accumulation of NF-κB was hampered by Iturin A. MD-2 siRNA or plasmid further confirmed the efficacy of Iturin A by suppressing MD-2/TLR4 signaling pathway. The in silico docking study showed that the Iturin A interacted well with the MD-2 in MD-2/TLR4 receptor complex. Conclusively, inhibition of MD-2/TLR4 complex with Iturin A offered strategic advancement in cancer therapy.

• Authors: Goutam Dey, Rashmi Bharti, Probir Kumar Ojha, Ipsita Pal, Y Rajesh, Indranil Banerjee, Payel Banik, Sheetal Parida, Aditya Parekh, Ramkrishna Sen, Mahitosh Mandal
• Journal: Cellular signalling (Cell Signal) Vol. 35 Pg. 24-36 (07 2017) ISSN: 1873-3913 [Electronic] England
• PMID: 28347875 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• LY96 protein, human
• Lymphocyte Antigen 96
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• NF-kappa B
• Peptides, Cyclic
• RNA, Small Interfering
• TLR4 protein, human
• Toll-Like Receptor 4
• iturin A
• CHUK protein, human
• I-kappa B Kinase

Topics

• Bacillus megaterium (chemistry)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• I-kappa B Kinase (genetics)
• Lymphocyte Antigen 96 (chemistry, genetics)
• Myeloid Differentiation Factor 88 (genetics)
• NF-kappa B (genetics)
• Neoplasm Invasiveness (genetics)
• Neoplasms (drug therapy, genetics, pathology)
• Neovascularization, Pathologic (drug therapy, genetics, pathology)
• Peptides, Cyclic (administration & dosage, chemistry)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects)
• Toll-Like Receptor 4 (chemistry, genetics)