Prolactin stimulates cell proliferation through a long form of prolactin receptor and K+ channel activation.
PRL (prolactin) has been implicated in the proliferation and differentiation of numerous tissues, including the prostate gland. However, the PRL-R (PRL receptor) signal transduction pathway, leading to the stimulation of cell proliferation, remains unclear and has yet to be mapped. The present study was undertaken to develop a clear understanding of the mechanisms involved in this pathway and, in particular, to determine the role of K(+) channels. We used androgen-sensitive prostate cancer (LNCaP) cells whose proliferation is known to be stimulated by PRL. Reverse transcriptase PCR analysis showed that LNCaP cells express a long form of PRL-R, but do not produce its intermediate isoform. Patch-clamp techniques showed that the application of 5 nM PRL increased both the macroscopic K(+) current amplitude and the single K(+)-channel open probability. This single-channel activity increase was reduced by the tyrosine kinase inhibitors genistein, herbimycin A and lavandustine A, thereby indicating that tyrosine kinase phosphorylation is required in PRL-induced K(+) channel stimulation. PRL enhances p59( fyn ) phosphorylation by a factor of 2 after a 10 min application in culture. In addition, where an antip59( fyn ) antibody is present in the patch pipette, PRL no longer increases K(+) current amplitude. Furthermore, the PRL-stimulated proliferation is inhibited by the K(+) channel inhibitors alpha-dendrotoxin and tetraethylammonium. Thus, as K(+) channels are known to be involved in LNCaP cell proliferation, we suggest that K(+) channel modulation by PRL, via p59( fyn ) pathway, is the primary ionic event in PRL signal transduction, triggering cell proliferation.
Van Coppenolle
Fabien
F
Laboratoire de Physiologie Cellulaire, INSERM EMI 0228, Université des Sciences et Technologies de Lille, Bât. SN3, 59655 Villeneuve d'Ascq Cedex, France.
Skryma
Roman
R
Ouadid-Ahidouch
Halima
H
Slomianny
Christian
C
Roudbaraki
Morad
M
Delcourt
Philippe
P
Dewailly
Etienne
E
Humez
Sandrine
S
Crépin
Alexandre
A
Gourdou
Isabelle
I
Djiane
Jean
J
Bonnal
Jean-Louis
JL
Mauroy
Brigitte
B
Prevarskaya
Natalia
N
D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003600:Cytosol / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D011981:Receptors, Prolactin / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D009363:Neoplasm Proteins; D015221:Potassium Channels; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D011388:Prolactin; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D002118:Calcium