Cytomodulin-1, a synthetic peptide abrogates oncogenic signaling pathways to impede invasion and angiogenesis in the hamster cheek pouch carcinogenesis model
Constitutive activation of the various oncogenic signaling pathways plays a pivotal role in promoting malignant transformation. The aim of this study was to investigate the therapeutic potential of a synthetic bioactive heptapeptide cytomodulin-1 (CM-1) against hamster cheek pouch carcinomas based o...
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Veröffentlicht in: | Biochimie 2014-07, Vol.102, p.56-67 |
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Sprache: | eng |
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Zusammenfassung: | Constitutive activation of the various oncogenic signaling pathways plays a pivotal role in promoting malignant transformation. The aim of this study was to investigate the therapeutic potential of a synthetic bioactive heptapeptide cytomodulin-1 (CM-1) against hamster cheek pouch carcinomas based on its influence on the predominant carcinogenic signaling pathways – NF-κB, TGFβ, and Wnt/β-catenin and their downstream target events invasion and angiogenesis. Topical application of CM-1 to DMBA-painted hamsters significantly inhibited activation of the canonical NF-κB pathway by blocking kinase activity of IKKβ and increasing the cytosolic accumulation of the inhibitor IκB-α. In addition, CM-1 inactivated IKKβ by disrupting IKKβ/Nemo interactions. CM-1 also hampered the activation of TGFβ and Wnt/β-catenin signaling by averting the phosphorylation of the key upstream ser/thr kinases TGFβ RI and GSK-3β respectively. Attenuation of these oncogenic signaling pathways by CM-1 also mitigated invasion and angiogenesis by suppressing the expression of pro-invasive matrix metalloproteinases, pro-angiogenic VEGF and HIF-1α and upregulating the anti-angiogenic TIMP-2. Synthetic peptides such as CM-1 that target multiple key molecules in oncogenic signaling pathways and their downstream events are ideal candidate agents for cancer chemotherapy.
•Cytomodulin-1 inhibits the development of HBP carcinomas by abrogating activation of oncogenic signaling pathways.•CM-1 attenuates NF-κB, TGFβ, and Wnt/β-catenin signaling by preventing the activation of upstream kinases.•CM-1 also blocks invasion and angiogenesis. |
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ISSN: | 0300-9084 1638-6183 |
DOI: | 10.1016/j.biochi.2014.02.010 |