A Novel Role of Dickkopf-Related Protein 3 in Macropinocytosis in Human Bladder Cancer T24 Cells

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.

Meridianin C inhibits the growth of YD‐10B human tongue cancer cells through macropinocytosis and the down‐regulation of Dickkopf‐related protein‐3

“…DKK‐3 plays a role in modulating macropinocytosis in T24 human bladder cancer cells and is also expressed in OSCC‐derived cell lines . We therefore sought to explore whether DKK‐3 is expressed in YD‐10B cells and is regulated by meridianin C treatment.…”

“…DKK-3 knock-down by siRNA in T24 human bladder cancer cells inhibited cell growth and induced macropinocytosis and autophagy. 16 It also has been recently demonstrated that DKK-3 is expressed in a subset of OSCC-derived cell lines including HSC-4. 33 Moreover, in…”

“…7 Multiple proteins and signalling factors are involved in macropinocytosis, including the Rho superfamily of GTPases (Rac, Cdc42), lipid components (phosphoinositides, cholesterol, phosphatidylinositol phosphates), phospholipid kinases, receptor tyrosine kinases and phosphatases, SNX-5 and DKK-3. [8][9][10][11][12][13][14][15][16] There is also large body of evidence that now shows macropinocytosis can be specifically activated by extracellular stimuli, such as growth factors and natural or synthetic chemicals, and the activated macropinocytosis can have effects on cell survival/proliferation or cell death/growth inhibition on distinct cell types including cancer cells. 17,18 Meridianin C is one of the marine derived indole alkaloids (meridianin A-G) isolated from the South Atlantic tunicate Aplidium meridianum.…”

MiR-425 Promotes Migration and Invasion in Bladder Cancer by Targeting Dickkopf 3

“…Notably, it has been observed that reducing and/or silencing Dkk3 is closely related to a broad range of cancer cell types, including BC (7,8). However, Tsujimura et al (9) demonstrated that the expression of Dkk-3 was exceptionally increased in BC. These findings collectively indicated that DKK3 plays a critical role in the progression of BC.…”

Dickkopf homolog 3 (DKK3): A candidate for detection and treatment of cancers?

“…Initially, DKK3 was recognized as a tumor suppressor and was also revealed to be involved in epithelial cell senescence and acinar cell differentiation and morphogenesis (Tsujimura et al, ). Based on several studies, DKK3 has been shown to play a key role in remodeling of tumor vasculature and is likely involved in capillary formation and angiogenesis (Untergasser, Martowicz, Hermann, Töchterle, & Meyer, ).…”