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Imaging Mitogen-Activated Protein Kinase Function in Xenograft Models of Prostate Cancer

Departments of ¹ Biological Chemistry, ² Urology, ³ Molecular and Medical Pharmacology and Medicine, and ⁴ Medicine-Hematology and Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Michael Carey, Department of Biological Chemistry, University of California at Los Angeles, 10833 Le Conte Avenue, CHS 33-142, Los Angeles, CA 90095-1737. Phone: 310-206-7859; Fax: 310-206-5272; E-mail: mcarey{at}mednet.ucla.edu.

Mitogen-activated protein kinases (MAPK) play important roles in malignancy. The ability to detect and quantitate MAPKs in live animal models of cancer will facilitate an understanding of disease progression. We have developed a gene expression-based imaging system that detects and quantifies MAPK activity in prostate cancer tumors implanted into severe combined immunodeficient mice. The imaging technology uses a modified version of two-step transcriptional amplification (TSTA). The tissue specificity of gene expression is imparted by an enhanced version of the prostate-specific antigen regulatory region that expresses GAL4-ELK1. GAL4-ELK1 confers MAPK specificity by activating a firefly luciferase (FLuc) reporter gene when the Ets-like transcription factor (ELK) 1 activation domain is phosphorylated by MAPK. FLuc activity in live animals was detected using the Xenogen In vivo Imaging System. We validated the TSTA-ELK1 system by analyzing its response to epidermal growth factor treatment in transfected tissue culture cells and in adenovirus (AdTSTA-ELK1)–injected prostate cancer xenograft tumors. We measured MAPK activity in two well-characterized xenograft models, CWR22 and LAPC9. Although no significant differences in MAPK levels were detected between androgen-dependent and androgen-independent xenografts, the CWR22 models display significantly higher levels of AdTSTA-ELK1 activity versus LAPC9. Western blots of tumor extracts showed that the elevated imaging signal in CWR22 xenografts correlated with elevated levels of phosphorylated extracellular signal-regulated kinase 1/2 but not p38 or c-Jun NH₂-terminal kinase. We conclude that a gene expression-based optical imaging system can accurately detect and quantify MAPK activity in live animals. (Cancer Res 2006; 66(22): 10778-85)