Intermediate Ca2+-sensitive K+ channels are necessary for prolactin-induced proliferation in breast cancer cells.
Prolactin (PRL) is a polypeptidic hormone which acts both systemically and locally to cause lactation by interacting with the PRL receptor, a Janus kinase (JAK2)-coupled cytokine receptor family member. Several studies have reported that serum PRL level elevation is associated with an increased risk for breast cancer, and evidence has suggested that PRL is one actor in the pathogenesis and progression of this cancer. We previously reported the involvement of hIKCa1 in breast cell cycle progression and cell proliferation. However, mechanisms by which PRL cooperates with these channels to modulate breast epithelial cell proliferation remain unknown. Our results showed that, in the MCF-7 breast cancer cell line, PRL increased hIKCa1 current density. These channels were functional and regulated the resting membrane potential. The PRL effects were inhibited by TRAM-34 and clotrimazole, the most used hIKCa1 blockers. Moreover, PRL increased proliferation in a dose-dependent manner without overexpressing hIKCa1. To determine whether PRL-induced proliferation and hIKCa1 activity involved the JAK2 pathway, we used pharmacological JAK2 inhibitors (AG490 and JAK inhibitor I). Indeed, PRL-induced JAK2 phosphorylation was required for both cell proliferation and hIKCa1 activity. In the presence of either hIKCa1 blockers or siRNA-hIKCa1, PRL failed to increase cell proliferation and hIKCa1 activity. Taken together, our results demonstrate that PRL plays a role in breast cancer cell proliferation by increasing hIKCa1 activity through the JAK2 signaling pathway.
Faouzi
Malika
M
Laboratoire de Physiologie Cellulaire et Moléculaire, Université de Picardie Jules Verne, 80000 Amiens, France.
Chopin
Valérie
V
Ahidouch
Ahmed
A
Ouadid-Ahidouch
Halima
H
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003022:Clotrimazole / Q000494:pharmacology; D005260:Female; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*; D053614:Janus Kinase 2 / Q000502:physiology*; D011388:Prolactin / Q000494:pharmacology; D011720:Pyrazoles; D011981:Receptors, Prolactin / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D011720:Pyrazoles; D011981:Receptors, Prolactin; C411671:TRAM 34; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011388:Prolactin; D053614:Janus Kinase 2; D003022:Clotrimazole; D002118:Calcium