Prolyl isomerase cyclophilin A regulation of Janus-activated kinase 2 and the progression of human breast cancer.
The activation of the Janus-activated kinase 2 (Jak2) tyrosine kinase following ligand binding has remained incompletely characterized at the mechanistic level. We report that the peptidyl-prolyl isomerase (PPI) cyclophilin A (CypA), which is implicated in the regulation of protein conformation, is necessary for the prolactin (PRL)-induced activation of Jak2 and the progression of human breast cancer. A direct correlation was observed between the levels or activity of CypA and the extent of PRL-induced signaling and gene expression. Loss of PRLr-CypA binding, following treatment with the PPI inhibitor cyclosporine A (CsA), or overexpression of a dominant-negative PRLr mutant (P334A) resulted in a loss of PRLr/Jak2-mediated signaling. In vitro, CsA treatment of breast cancer cells inhibited their growth, motility, invasion, and soft agar colony formation. In vivo, CsA treatment of nude mice xenografted with breast cancer cells induced tumor necrosis and completely inhibited metastasis. These studies reveal that a CypA-mediated conformational change within the PRLr/Jak2 complex is required for PRL-induced transduction and function and indicate that the inhibition of prolyl isomerases may be a novel therapeutic strategy in the treatment of human breast cancer.
Zheng
Jiamao
J
Department of Pathology, Breast Cancer Program, Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
Koblinski
Jennifer E
JE
Dutson
Laura V
LV
Feeney
Yvonne B
YB
Clevenger
Charles V
CV
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000037:antagonists & inhibitors / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D018450:Disease Progression; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000502:physiology; D011388:Prolactin / Q000494:pharmacology; D014183:Transplantation, Heterologous
D004791:Enzyme Inhibitors; D016572:Cyclosporine; D011388:Prolactin; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase