Receptor-mediated folate uptake is positively regulated by disruption of the actin cytoskeleton

Cheryl M. Lewis, Angela K. Smith, Barton A. Kamen

Research output: Contribution to journalArticle

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Abstract

Receptor-mediated folate uptake is initiated by binding of ligand to a glycosyl phosphatidylinositol-anchored protein, folate receptor α (FRα). This receptor is expressed in a limited number of normal tissues but is overexpressed in a large number of epithelial malignancies. FRα synthesis, at least in part, is regulated by endogenous folate and by hormones in some cells, but much less is known about the control of function. Recently, we showed that phorbol 12-myristate 13-acetate increases the rate of receptor cycling, increases the rate of folate delivery, and causes the majority of the receptor to reside on the cell surface in nonmalignant cells in vitro (C. M. Lewis et al., Biochim. Biophys. Acta, 1401: 157-169, 1998). However, based upon effects (or lack of effects) of specific inhibitors of protein kinase C, the mechanism of action of phorbol 12-myristate 13-acetate is not likely via protein kinase C. Because exo- and endocytosis are controlled by the actin cytoskeleton, we tested cytochalasin D and latrunculin B, actin-disrupting agents, on FRα-mediated folate uptake. Disruption of the actin cytoskeleton reversibly increases the proportion of receptors on the cell surface and increases the rate of 5-methyltetrahydrofolate delivery. Disrupting microtubules with nocodazole had no effect. The increased rate of folate delivery caused by cytochalasin D is not observed in FR-negative cell lines. Although we have not yet identified the upstream effectors, likely candidates include small G-proteins such as rho, which are known to cause actin polymerization. In addition to identifying the machinery for receptor- mediated folate uptake, it may be important to integrate this new data into studies of FRα as a tumor antigen for imaging or delivering molecules via anti-FR antibodies or compounds coupled to folic acid.

Original languageEnglish (US)
Pages (from-to)2952-2956
Number of pages5
JournalCancer Research
Volume58
Issue number14
StatePublished - Jul 15 1998

Fingerprint

Actin Cytoskeleton
Folic Acid
Cytochalasin D
Protein Kinase C
Actins
Acetates
Nocodazole
Glycosylphosphatidylinositols
Cytochalasin B
Monomeric GTP-Binding Proteins
Exocytosis
Cell Surface Receptors
Neoplasm Antigens
Endocytosis
Microtubules
Polymerization
Hormones
Ligands

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Receptor-mediated folate uptake is positively regulated by disruption of the actin cytoskeleton. / Lewis, Cheryl M.; Smith, Angela K.; Kamen, Barton A.

In: Cancer Research, Vol. 58, No. 14, 15.07.1998, p. 2952-2956.

Research output: Contribution to journalArticle

Lewis, Cheryl M. ; Smith, Angela K. ; Kamen, Barton A. / Receptor-mediated folate uptake is positively regulated by disruption of the actin cytoskeleton. In: Cancer Research. 1998 ; Vol. 58, No. 14. pp. 2952-2956.
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