GSK3β inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation.
This study addresses the role of glycogen synthase kinase (GSK)-3β signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3β to be focally expressed in the invasive portions of 12 and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and small interfering RNA (siRNA) knockdown of GSK3β were found to inhibit the motile behavior of melanoma cells in scratch wound, three-dimensional collagen-implanted spheroid, and modified Boyden chamber assays. Functionally, inhibition of GSK3β signaling was found to suppress N-cadherin expression at the messenger RNA and protein levels, and was associated with decreased expression of the transcription factor Slug. Pharmacological and genetic ablation of GSK3β signaling inhibited the adhesion of melanoma cells to both endothelial cells and fibroblasts and prevented transendothelial migration, an effect rescued by the forced overexpression of N-cadherin. A further role for GSK3β signaling in invasion was suggested by the ability of GSK3β inhibitors and siRNA knockdown to block phosphorylation of focal adhesion kinase (FAK) and increase the size of focal adhesions. In summary, we have, to our knowledge, demonstrated a previously unreported role for GSK3β in modulating the motile and invasive behavior of melanoma cells through N-cadherin and FAK. These studies suggest the potential therapeutic utility of inhibiting GSK3β in defined subsets of melanoma.
Department of Molecular Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Jobin K
JK
John
Kim H T
KH
Paraiso
Vito W
VW
Rebecca
Liliana P
LP
Cantini
Ethan V
EV
Abel
Nicholas
N
Pagano
Eric
E
Meggers
Rahel
R
Mathew
Clemens
C
Krepler
Victoria
V
Izumi
Bin
B
Fang
John M
JM
Koomen
Jane L
JL
Messina
Meenhard
M
Herlyn
Keiran S M
KS
Smalley
D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D022001:Focal Adhesions / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology
D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3