Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition.
Carcinoma progression is associated with the loss of epithelial features, and the acquisition of mesenchymal characteristics and invasive properties by tumour cells. The loss of cell-cell contacts may be the first step of the epithelium mesenchyme transition (EMT) and involves the functional inactivation of the cell-cell adhesion molecule E-cadherin. Repression of E-cadherin expression by the transcription factor Snail is a central event during the loss of epithelial phenotype. Akt kinase activation is frequent in human carcinomas, and Akt regulates various cellular mechanisms including EMT. Here, we show that Snail activation and consequent repression of E-cadherin may depend on AKT-mediated nuclear factor-kappaB (NF-kappaB) activation, and that NF-kappaB induces Snail expression. Expression of the NF-kappaB subunit p65 is sufficient for EMT induction, validating this signalling module during EMT. NF-kappaB pathway activation is associated with tumour progression and metastasis of several human tumour types; E-cadherin acts as a metastasis suppressor protein. Thus, this signalling and transcriptional network linking AKT, NF-kappaB, Snail and E-cadherin during EMT is a potential target for antimetastatic therapeutics.
Julien
S
S
1Developmental Genetics of Melanocytes, UMR 146 CNRS-Institut Curie, Bat. 110, Orsay Cedex, France.
Puig
I
I
Caretti
E
E
Bonaventure
J
J
Nelles
L
L
van Roy
F
F
Dargemont
C
C
de Herreros
A Garcia
AG
Bellacosa
A
A
Larue
L
L
D000818:Animals; D015820:Cadherins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D008648:Mesoderm / Q000473:pathology; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000074165:Zinc Finger E-box Binding Homeobox 2
D015820:Cadherins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA; D014157:Transcription Factors; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D051057:Proto-Oncogene Proteins c-akt