α-Catulin downregulates E-cadherin and promotes melanoma progression and invasion.
Metastasis is associated with poor prognosis for melanoma responsible for about 90% of skin cancer-related mortality. To metastasize, melanoma cells must escape keratinocyte control, invade across the basement membrane and survive in the dermis by resisting apoptosis before they can intravasate into the circulation. α-Catulin (CTNNAL1) is a cytoplasmic molecule that integrates the crosstalk between nuclear factor-kappa B and Rho signaling pathways, binds to β-catenin and increases the level of both α-catenin and β-catenin and therefore has potential effects on inflammation, apoptosis and cytoskeletal reorganization. Here, we show that α-catulin is highly expressed in melanoma cells. Expression of α-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. Knockdown of α-catulin promoted adhesion to and inhibited migration away from keratinocytes in an E-cadherin-dependent manner and decreased the transmigration through a keratinocyte monolayer, as well as in Transwell assays using collagens, laminin and fibronectin coating. Moreover, knockdown promoted homotypic spheroid formation and concomitantly increased E-cadherin expression along with downregulation of transcription factors implicated in its repression (Snail/Slug, Twist and ZEB). Consistent with the molecular changes, α-catulin provoked invasion of melanoma cells in a three-dimensional culture assay by the upregulation of matrix metalloproteinases 2 and 9 and the activation of ROCK/Rho. As such, α-catulin may represent a key driver of the metastatic process, implicating potential for therapeutic interference.
Medical and Pharmaceutical Biotechnology, University of Applied Sciences, Krems, Austria.
Birgit
B
Kreiseder
Lukas
L
Orel
Constantin
C
Bujnow
Stefan
S
Buschek
Maren
M
Pflueger
Wolfgang
W
Schuett
Harald
H
Hundsberger
Rainer
R
de Martin
Christoph
C
Wiesner
D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D004817:Epidermis / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000556:secondary; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000096:biosynthesis; D015533:Transcriptional Activation; D015854:Up-Regulation; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
C495274:CTNNAL1 protein, human; D015820:Cadherins; D016328:NF-kappa B; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051178:alpha Catenin; D051176:beta Catenin; D054460:rho-Associated Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9