Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB

Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012...

Full description

Saved in:
Bibliographic Details
Published inPloS one Vol. 6; no. 6; p. e21496
Main Authors Eberle, Karen E, Sansing, Hope A, Szaniszlo, Peter, Resto, Vicente A, Berrier, Allison L
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 24.06.2011
Public Library of Science (PLoS)
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary:Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β₁ was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β₁, talin and FAK pathways that regulate NF-kB nuclear activity.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceived and designed the experiments: ALB VAR PS. Performed the experiments: ALB KEE HAS PS. Analyzed the data: ALB HAS PS VAR. Contributed reagents/materials/analysis tools: ALB VAR PS. Wrote the paper: ALB PS.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0021496