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

FEBS Open Bio. 2020 Dec;10(12):2722-2732. doi: 10.1002/2211-5463.13008. Epub 2020 Nov 3.


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.

Keywords: LPS; TLR4; adhesion; endocytosis; fetuin-A; receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Adhesion
  • Cell Line, Tumor
  • Endocytosis
  • Humans
  • Toll-Like Receptor 4 / metabolism*
  • alpha-2-HS-Glycoprotein / metabolism*


  • TLR4 protein, human
  • Toll-Like Receptor 4
  • alpha-2-HS-Glycoprotein