Activation of signal transducer and activator of transcription 5 in human prostate cancer is associated with high histological grade.
We have recently identified signal transducer and activator of transcription 5 (Stat5) as a critical survival factor for prostate cancer cells. We now report that activation of Stat5 is associated with high histological grade of human prostate cancer. Specifically, immunohistochemical analysis demonstrated a strong positive correlation with activation of Stat5 and high Gleason score in 114 human prostate cancers. To investigate the mechanisms underlying constitutive activation of Stat5 in prostate cancer, a dominant-negative mutant of Janus kinase 2 (Jak2) was delivered by adenovirus to CWR22Rv cells. Dominant-negative-Jak2 effectively blocked the activation of Stat5 whereas wild-type Jak2 enhanced activation, indicating that Jak2 is the main kinase that phosphorylates Stat5 in human prostate cancer cells. A ligand-induced mechanism for activation of Stat5 in prostate cancer was suggested by the ability of prolactin (Prl) to stimulate activation of both Jak2 and Stat5 in CWR22Rv human prostate cancer cells and in CWR22Rv xenograft tumors. In addition, Prl restored constitutive activation of Stat5 in five of six human prostate cancer specimens in ex vivo long-term organ cultures. Finally, Prl protein was locally expressed in the epithelium of 54% of 80 human prostate cancer specimens with positive correlation with high Gleason scores and activation of Stat5. In conclusion, our data indicate that increased activation of Stat5 was associated with more biologically aggressive behavior of prostate cancer. The results further suggest that Jak2 is the principal Stat5 tyrosine kinase in human prostate cancer, possibly activated by autocrine/paracrine Prl.
Li
Hongzhen
H
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NRB E508, 3970 Reservoir Road NW, Washington, DC 20057, USA.
Ahonen
Tommi J
TJ
Alanen
Kalle
K
Xie
Jianwu
J
LeBaron
Matthew J
MJ
Pretlow
Thomas G
TG
Ealley
Erica L
EL
Zhang
Ying
Y
Nurmi
Martti
M
Singh
Baljit
B
Martikainen
Paula M
PM
Nevalainen
Marja T
MT
D000368:Aged; D000818:Animals; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008894:Milk Proteins; D009368:Neoplasm Transplantation; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011388:Prolactin / Q000096:biosynthesis / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011388:Prolactin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2