Restoration of E-cadherin sensitizes human melanoma cells for apoptosis.
Cell-cell adhesion is considered to be important in the development and maintenance of organ tissue. The spatial association between melanocytes and keratinocytes within human epidermis is achieved by homophilic interaction of E-cadherin molecules located on adjacent cells. In contrast, downregulation of E-cadherin expression in melanoma cells is considered as a key event in metastasis. Besides the adhesive properties, E-cadherin serves as a signal receptor linking to the cadherin-catenin signaling complex. As cadherins act as negative regulators of beta-catenin, a contribution to tumor formation seems likely. In the present study, it was tested whether ectopic expression of E-cadherin triggers apoptosis in human melanoma cell lines (G-361, JPC-298, SK-Mel-13). It was found that restoration of E-cadherin caused sensitization against drug-induced apoptosis. Particularly, the release of mitochondrial cytochrome c was increased in response to staurosporine. Moreover, activation of caspase-3 and caspase-8 was elevated. Similarly, DNA fragmentation, serving as a marker for advanced apoptosis, was amplified in cells transduced with E-cadherin. Interestingly, transduction with an E-cadherin construct lacking the extracellular domain showed no modified apoptosis. In conclusion, our findings suggest therapeutic strategies that enable expression of E-cadherin in order to sensitize human melanoma cells towards apoptosis.
Kippenberger
Stefan
S
Department of Dermatology, Division of Pneumology, University of Frankfurt Medical School, Frankfurt/Main, Germany. kippenberger@em.uni-frankfurt.de
Loitsch
Stefan
S
Thaçi
Diamant
D
Müller
Jutta
J
Guschel
Maike
M
Kaufmann
Roland
R
Bernd
August
A
D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D051177:Catenins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D009362:Neoplasm Metastasis; D017434:Protein Structure, Tertiary; D019311:Staurosporine / Q000494:pharmacology
D015820:Cadherins; D051177:Catenins; D045304:Cytochromes c; D053148:Caspase 3; D053181:Caspase 8; D019311:Staurosporine