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Am J Physiol Cell Physiol 289: C130-C137, 2005. First published March 9, 2005; doi:10.1152/ajpcell.00416.2004
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Autocrine production of prostaglandin F2{alpha} enhances phenotypic transformation of normal rat kidney fibroblasts

E. G. A. Harks,1 P. H. J. Peters,1 J. L. J. van Dongen,2 E. J. J. van Zoelen,1 and A. P. R. Theuvenet1

1Department of Cell Biology, Radboud University Nijmegen, Nijmegen; and 2Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, Eindhoven, The Netherlands

Submitted 24 August 2004 ; accepted in final form 11 February 2005

We have used normal rat kidney (NRK) fibroblasts as an in vitro model system to study cell transformation. These cells obtain a transformed phenotype upon stimulation with growth-modulating factors such as retinoic acid (RA) or transforming growth factor-{beta} (TGF-{beta}). Patch-clamp experiments showed that transformation is paralleled by a profound membrane depolarization from around –70 to –20 mV. This depolarization is caused by a compound in the medium conditioned by transformed NRK cells, which enhances intracellular Ca2+ levels and thereby activates Ca2+-dependent Cl– channels. This compound was identified as prostaglandin F2{alpha} (PGF2{alpha}) using electrospray ionization mass spectrometry. The active concentration in the medium conditioned by transformed NRK cells as determined using an enzyme immunoassay was 19.7 ± 2.5 nM (n = 6), compared with 1.5 ± 0.1 nM (n = 3) conditioned by nontransformed NRK cells. Externally added PGF2{alpha} was able to trigger NRK cells that had grown to density arrest to restart their proliferation. This proliferation was inhibited when the FP receptor (i.e., natural receptor for PGF2{alpha}) was blocked by AL-8810. RA-induced phenotypic transformation of NRK cells was partially (~25%) suppressed by AL-8810. Our results demonstrate that PGF2{alpha} acts as an autocrine enhancer and paracrine inducer of cell transformation and suggest that it may play a crucial role in carcinogenesis in general.

membrane potential; intracellular calcium; mass spectrometry; FP receptor


Address for reprint requests and other correspondence: A. P. R. Theuvenet, Dept. of Cell Biology, Radboud Univ. Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands






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