The rapid endocytic uptake of fetuin‐A by adherent tumor cells is mediated by Toll‐like receptor 4 (TLR4)

Fetuin‐A is a serum glycoprotein synthesized and secreted into blood by the liver and whose main physiological function is the inhibition of ectopic calcification. However, a number of studies have demonstrated that it is a multifunctional protein. For example, endocytic uptake of fetuin‐A by tumor cells resulting in rapid cellular adhesion and spreading has been reported. The precise uptake mechanism, however, has been elusive. The present studies were done to determine whether Toll‐like receptor‐4 (TLR4), which has been previously shown to be a receptor for fetuin‐A and is commonly expressed in immune cells, could take part in the rapid uptake (< 3 min) of fetuin‐A by tumor cells. Rapid uptake of fetuin‐A was inhibited by the specific TLR4 inhibitor CLI‐095 and also attenuated in TLR4 knockdown prostate tumor cells. Inhibition of TLR4 by CLI‐095 also attenuated the rapid adhesion of tumor cells as well as invasion through a bed of Matrigel. The data suggest mechanisms by which TLR4 modulates the adhesion and growth of tumor cells.