Abstract
Dickkopf-related protein 3 (Dkk-3) is a potential tumor suppressor reported in various cancer entities. However, we found that Dkk-3 was exceptionally upregulated in bladder cancer T24 cells. To validate the biological role of Dkk-3 other than a tumor suppressor, we examined the function of Dkk-3 in T24 cells. Gene silencing of Dkk-3 inhibited cell growth through inducing G0/G1 cell-cycle arrest. Furthermore, Dkk-3 knock-down caused macropinocytosis accompanied by autophagy, which were canceled in part by their inhibitors 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyladenine (3-MA). The macropinocytosis was induced by the Dkk-3 knock-down when there were sufficient extracellular nutrients. On the other hand, when the nutritional condition was poor, the autophagy was mainly induced by the Dkk-3 knock-down. These data indicated that Dkk-3 has a role in modulating macropinocytotic and autophagic pathways, a distinct function other than a Wnt antagonist.
Highlights
The Wnt signaling pathway regulates cell proliferation, differentiation, fate and death in multiple biological processes ranging from embryonic development to cancer progression [1]
We found that Dickkopf-related protein 3 (Dkk-3) is exceptionally overexpressed in T24 cells, and we focused on T24 cells to validate the function of endogenous Dickkopf-related protein (Dkk)-3 in this study
Dkk-3 protein expression was especially upregulated in human bladder cancer T24 cells
Summary
The Wnt signaling pathway regulates cell proliferation, differentiation, fate and death in multiple biological processes ranging from embryonic development to cancer progression [1]. The Dickkopf-related protein (Dkk) family is known as a secreted Wnt antagonist. Secreted Dkk binds to the LRP5/6, disrupts the formation of the Fz/LRP5/6 complex and inhibits Wnt/β-catenin signaling. It has been shown that Dkk-3 does not bind to LRP5/6 or affect Wnt/β-catenin signaling [3]. Some studies have demonstrated that Dkk-3 can antagonize Wnt and inhibit Wnt/β-catenin signaling [4,5,6]. The role of secreted Dkk-3 in the Wnt/β-catenin signaling is still elusive. Dkk-3 is called REIC (reduced expression in immortalized cells), because its endogenous expression is decreased in the immortalized cells [7]. Downregulation of endogenous Dkk-3/REIC is frequently observed in most cancers. Overexpression of Dkk-3 can induce apoptosis via c-jun N-terminal kinase (JNK)
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