Mitogen-Activated Protein Kinase Kinase Kinase 1 Activates Androgen Receptor-Dependent Transcription and Apoptosis in Prostate Cancer

Abstract

Mitogen-activated protein (MAP) kinases phosphorylate the estrogen receptor and activate transcription from estrogen receptor-regulated genes. Here we examine potential interactions between the MAP kinase cascade and androgen receptor-mediated gene regulation. Specifically, we have studied the biological effects of mitogen-activated protein kinase kinase kinase 1 (MEKK1) expression in prostate cancer cells. Our findings demonstrate that expression of constitutively active MEKK1 induces apoptosis in androgen receptor-positive but not in androgen receptor-negative prostate cancer cells. Reconstitution of the androgen receptor signaling pathway in androgen receptor-negative prostate cancer cells restores MEKK1-induced apoptosis. MEKK1 also stimulates the transcriptional activity of the androgen receptor in the presence or absence of ligand, whereas a dominant negative mutant of MEKK1 impairs activation of the androgen receptor by androgen. These studies demonstrate an unanticipated link between MEKK1 and hormone receptor signaling and have implications for the molecular basis of hormone-independent prostate cancer growth.

ACKNOWLEDGMENTS

We thank Michael Carey and Yuriy Shostak for assistance and reagents used to perform 4X-ARE/E4-CAT experiments and the ZEBRA reporter assay. We thank David Chang for use of a fluorescent microscope and helpful discussions. We thank Michael Karin, Marco Marcelli, and Arie Belldegrun for providing necessary plasmids.

This work was supported by grants from the James S. McDonnell Foundation, the Margaret Early Trust, and CapCURE. M.T.A.-M. was supported by a Crohn’s and Colitis Foundation of America Career Development Award. A.C. was supported by a Howard Hughes Medical Institute Medical Student Research Fellowship.