c-Jun N-terminal kinase inhibitor II (SP600125) activates Mullerian inhibiting substance type II receptor-mediated signal transduction.
Müllerian inhibiting substance (MIS), the hormone required for Müllerian duct regression in fetal males, is also expressed in both adult males and females, but its physiological role in these settings is not clear. The expression of the MIS type II receptor (MISRII) in ovarian cancer cells and the ability of MIS to inhibit proliferation of these cells suggest that MIS might be a promising therapeutic for recurrent ovarian cancer. Using an MISRII-dependent activity assay in a small-molecule screen for MIS-mimetic compounds, we have identified the c-Jun N-terminal kinase inhibitor SP600125 as an activator of the MIS signal transduction pathway. SP600125 increased the activity of a bone morphogenetic protein-responsive reporter gene in a dose-dependent manner and exerted a synergistic effect when used in combination with MIS. This effect was specific for the MISRII and was not seen with other receptors of the TGFbeta family. Moreover, treatment of mouse ovarian cancer cells with a combination of SP600125 and paclitaxel, an established chemotherapeutic agent used in the treatment of ovarian cancer, or with MIS enabled inhibition of cell proliferation at a lower dose than with each treatment alone. These results offer a strong rationale for testing the therapeutic potential of SP600125, alone or in combination with already established drugs, in the treatment of recurrent ovarian cancer with a much-needed decrease in the toxic side effects of currently employed therapeutic agents.
Renlund
Nina
N
Vincent Center for Reproductive Biology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
Pieretti-Vanmarcke
Rafael
R
O'Neill
Francis H
FH
Zhang
LiHua
L
Donahoe
Patricia K
PK
Teixeira
Jose
J
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D054304:Anti-Mullerian Hormone / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018000:Receptors, Peptide / Q000378:metabolism / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D000873:Anthracenes; D019485:Bone Morphogenetic Proteins; D004791:Enzyme Inhibitors; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; C432165:pyrazolanthrone; D054304:Anti-Mullerian Hormone; D048031:JNK Mitogen-Activated Protein Kinases