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Int. J. Mol. Sci. 2014, 15(12), 23705-23724; doi:10.3390/ijms151223705

Lunasin Sensitivity in Non-Small Cell Lung Cancer Cells Is Linked to Suppression of Integrin Signaling and Changes in Histone Acetylation

1
Owensboro Cancer Research Program, Mitchell Memorial Cancer Center, Owensboro, KY 42303, USA
2
James Graham Brown Cancer Center and Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA
Current address: Biotechnology Program, Simon Hall MSB, 212 S. Hawthorne Drive, Indiana University, Bloomington, IN 47405, USA.
*
Author to whom correspondence should be addressed.
Received: 29 September 2014 / Revised: 3 December 2014 / Accepted: 8 December 2014 / Published: 18 December 2014
(This article belongs to the Special Issue Bioactive Proteins and Peptides Derived from Food)
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Abstract

Lunasin is a plant derived bioactive peptide with both cancer chemopreventive and therapeutic activity. We recently showed lunasin inhibits non-small cell lung cancer (NSCLC) cell proliferation in a cell-line-specific manner. We now compared the effects of lunasin treatment of lunasin-sensitive (H661) and lunasin-insensitive (H1299) NSCLC cells with respect to lunasin uptake, histone acetylation and integrin signaling. Both cell lines exhibited changes in histone acetylation, with H661 cells showing a unique increase in H4K16 acetylation. Proximity ligation assays demonstrated lunasin interacted with integrins containing αv, α5, β1 and β3 subunits to a larger extent in the H661 compared to H1299 cells. Moreover, lunasin specifically disrupted the interaction of β1 and β3 subunits with the downstream signaling components phosphorylated Focal Adhesion Kinase (pFAK), Kindlin and Intergrin Linked Kinase in H661 cells. Immunoblot analyses demonstrated lunasin treatment of H661 resulted in reduced levels of pFAK, phosphorylated Akt and phosphorylated ERK1/2 whereas no changes were observed in H1299 cells. Silencing of αv expression in H661 cells confirmed signaling through integrins containing αv is essential for proliferation. Moreover, lunasin was unable to further inhibit proliferation in αv-silenced H661 cells. This indicates antagonism of integrin signaling via αv-containing integrins is an important component of lunasin’s mechanism of action. View Full-Text
Keywords: lunasin; lung cancer; integrin signaling; histone acetylation; cell proliferation; Akt signaling lunasin; lung cancer; integrin signaling; histone acetylation; cell proliferation; Akt signaling
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Inaba, J.; McConnell, E.J.; Davis, K.R. Lunasin Sensitivity in Non-Small Cell Lung Cancer Cells Is Linked to Suppression of Integrin Signaling and Changes in Histone Acetylation. Int. J. Mol. Sci. 2014, 15, 23705-23724.

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