Published online before print May 15, 2008

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(American Journal of Pathology. 2008;172:1717-1728.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071054

Stat3 Promotes Metastatic Progression of Prostate Cancer

Junaid Abdulghani^*, Lei Gu^*, Ayush Dagvadorj^*, Jacqueline Lutz^*, Benjamin Leiby, Gloria Bonuccelli^*, Michael P. Lisanti^*, Tobias Zellweger, Kalle Alanen, Tuomas Mirtti, Tapio Visakorpi^¶, Lukas Bubendorf^|| and Marja T. Nevalainen^*

From the Department of Cancer Biology,^* Kimmel Cancer Center, and the Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania; the Department of Urology, St. Clara Hospital, Basel, Switzerland; the Institute for Pathology,|| University Hospital Basel, Basel, Switzerland; the Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland; and the Institute of Medical Technology,^¶ University of Tampere and Tampere University Hospital, Tampere, Finland

There are currently no effective therapies for metastatic prostate cancer because the molecular mechanisms that underlie the metastatic spread of primary prostate cancer are unclear. Transcription factor Stat3 is constitutively active in malignant prostate epithelium, and its activation is associated with high histological grade and advanced cancer stage. In this work, we hypothesized that Stat3 stimulates metastatic progression of prostate cancer. We show that Stat3 is active in 77% of lymph node and 67% of bone metastases of clinical human prostate cancers. Importantly, adenoviral gene delivery of wild-type Stat3 (AdWTStat3) to DU145 human prostate cancer cells increased the number of lung metastases by 33-fold in an experimental metastasis assay compared with controls. Using various methods to inhibit Stat3, we demonstrated that Stat3 promotes human prostate cancer cell migration. Stat3 induced the formation of lamellipodia in both DU145 and PC-3 cells, further supporting the concept that Stat3 promotes a migratory phenotype of human prostate cancer cells. Moreover, Stat3 caused the rearrangement of cytoplasmic actin stress fibers and microtubules in both DU145 and PC-3 cells. Finally, inhibition of the Jak2 tyrosine kinase decreased both activation of Stat3 and prostate cancer cell motility. Collectively, these data indicate that transcription factor Stat3 is involved in metastatic behavior of human prostate cancer cells and may provide a therapeutic target to prevent metastatic spread of primary prostate cancer.

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