Stat3 promotes metastatic progression of prostate cancer. Am J Pathol 2008 Jun;172(6):1717-28
Date
05/17/2008Pubmed ID
18483213Pubmed Central ID
PMC2408430DOI
10.2353/ajpath.2008.071054Scopus ID
2-s2.0-44849135184 (requires institutional sign-in at Scopus site) 224 CitationsAbstract
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.
Author List
Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Nevalainen MTMESH terms used to index this publication - Major topics in bold
Actin CytoskeletonAnimals
Bone Neoplasms
Cell Line, Tumor
Cell Movement
Humans
Janus Kinase 2
Lung Neoplasms
Lymphatic Metastasis
Male
Mice
Mice, Nude
Neoplasm Recurrence, Local
Neoplasm Transplantation
Prostatic Neoplasms
Pseudopodia
STAT3 Transcription Factor
Signal Transduction
rho GTP-Binding Proteins
