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The p38 Kinases MKK4 and MKK6 Suppress Metastatic Colonization in Human Ovarian Carcinoma

Departments of ¹ Biochemistry and Molecular Biology, ² Health Studies; ³ Committee on Cancer Biology; ⁴ Ben May Cancer Research Institute; ⁵ Section of Urology, Department of Surgery; and ⁶ Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois

Requests for reprints: S. Diane Yamada, Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, 5841 South Maryland Avenue, MC 2050 Chicago, IL 60637. Phone: 773-702-6721; Fax: 773-702-5411; E-mail: sdyamada{at}babies.bsd.uchicago.edu.

Despite considerable efforts to improve early detection of ovarian cancer, the majority of women at time of diagnosis will have metastatic disease. Understanding and targeting the molecular underpinnings of metastasis continues to be the principal challenge in the clinical management of ovarian cancer. Whereas the multistep process of metastasis development has been well established in both clinical and experimental models, the molecular factors and signaling pathways involved in successful colonization of a secondary site by disseminated cancer cells are not well defined. We have previously identified mitogen-activated protein kinase (MAPK) kinase 4/c-Jun NH₂-terminal kinase (JNK)-activating kinase (MKK4/JNKK1/SEK1, hereafter referred to as MKK4) as a metastasis suppressor protein in ovarian carcinoma. In this study, we elucidate key mechanisms of MKK4-mediated metastasis suppression. Through the use of a kinase-inactive mutant, we show that MKK4 kinase activity is essential for metastasis suppression and prolongation of animal survival. Because MKK4 can activate either of two MAPKs, p38 or JNK, we expressed MKK6 or MKK7, specific activators of these MAPKs, respectively, to delineate which MAPK signaling module was involved in MKK4-mediated metastasis suppression. We observed that MKK6 expression suppressed metastatic colonization whereas MKK7 had no effect. Our finding that MKK4 and MKK6 both suppress metastasis points to the p38 pathway as an important regulatory pathway for metastatic colonization in ovarian cancer. (Cancer Res 2006; 66(4): 2264-70)

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