糖原合成酶激酶-3（glycogen synthase kinase-3,，GSK-3）是一種多功能的絲氨酸／蘇氨酸蛋白激酶，是細(xì)胞內(nèi)多種信號(hào)轉(zhuǎn)導(dǎo)通路中的重要成分,，不僅參與細(xì)胞內(nèi)糖代謝過(guò)程而且還參與細(xì)胞增殖,、細(xì)胞分化和細(xì)胞凋亡等多種重要生理過(guò)程。
一項(xiàng)最新研究主要集中于分析糖原合酶激酶（GSK）-3β信號(hào)在黑色素瘤中的作用,。免疫組化染色顯示在原位和轉(zhuǎn)移性黑色素瘤組織中GSK3β的表達(dá)分別為12和33％,。
研究發(fā)現(xiàn)GSK3抑制劑及小干擾RNA（siRNA）降低GSK3β表達(dá)能抑制黑色素細(xì)胞的運(yùn)動(dòng)能力，這一效應(yīng)在劃痕實(shí)驗(yàn),、三維膠原蛋白植入球體以及改良Boyden小室實(shí)驗(yàn)中檢測(cè)到,。
進(jìn)一步探究證實(shí)抑制GSK3β信號(hào)降低N-cadherin的mRNA和蛋白表達(dá)水平，同時(shí)轉(zhuǎn)錄因子Slug的表達(dá)也下降,。抑制GSK3β信號(hào)也能抑制黑色素細(xì)胞與內(nèi)皮細(xì)胞和成纖維細(xì)胞之間的黏附,，防止黑色素瘤細(xì)胞跨內(nèi)皮遷移，而一旦恢復(fù)N-cadherin表達(dá),，上述效應(yīng)被逆轉(zhuǎn),。
GSK3β信號(hào)在黑色素瘤粘附中的作用主要通過(guò)調(diào)控粘著斑激酶（FAK）的磷酸化?？傊?，GSK3β通過(guò)影響N-cadherin和FAK調(diào)節(jié)黑色素細(xì)胞的運(yùn)動(dòng)性和侵襲能力。這些研究表明,，抑制GSK3β是一種潛在的黑色素瘤治療方法,。（生物谷：Bioon.com）
編譯自：GSK3β Inhibition Blocks Melanoma Cell/Host Interactions by Downregulating N-Cadherin Expression and Decreasing FAK Phosphorylation
doi:10.1038/jid.2012.237
PMC:
PMID:
GSK3β Inhibition Blocks Melanoma Cell/Host Interactions by Downregulating N-Cadherin Expression and Decreasing FAK Phosphorylation
Jobin K John, Kim H T Paraiso, Vito W Rebecca, Liliana P Cantini, Ethan V Abel, Nicholas Pagano, Eric Meggers, Rahel Mathew, Clemens Krepler, Victoria Izumi, Bin Fang, John M Koomen, Jane L Messina, Meenhard Herlyn and Keiran S M Smalley
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.
