C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma.
OBJECTIVE
C-Jun NH(2)-terminal kinase (JNK) has been implicated in numerous functions including stress responses, apoptosis,and transformation. The role in transformation is based largely on studies of isolated cell types with little indication of whether JNK plays a general role in a specific human tumor type or whether this occurs in vivo.


METHODS
We examined 9 human prostate carcinoma cell lines in vitro and a representative line in vivo.


RESULTS
For all of the cell lines proliferation is highly correlated with serum-supported JNK activity (r(Pearson) = 0.91; P = 0.004), whereas no relationship was observed for 10 human breast cancer cell lines (r(Pearson) = -0.32). Treatment with characterized antisense oligonucleotides complementary to sequences common to either the JNK1 or JNK2 family of isoforms showed that, whereas antisense JNK1 inhibited growth by a maximum of 57%, antisense JNK2 inhibited proliferation up to 80%. Sense and scrambled control oligonucleotides had little effect (average 3.7 +/- 1.5%). Moreover, systemic treatment of mice bearing established xenografts of PC3 prostate carcinoma cells with antisense JNK1 and JNK2 led to inhibition tumor growth by 57% (P < 0.002) and 80% (P < 0.001), respectively. The difference is significant (P < 0.012). Combined antisense treatment led to a significant increase in frequency of tumor regression (P = 0.022).


CONCLUSIONS
These results indicate that JNK is required for growth of prostate carcinoma cells in vitro and in vivo, and additionally indicate that JNK2 plays a dominant role. The JNK pathway is a novel target in the treatment of prostate carcinoma.
Yang
Yong-Min
YM
Sidney Kimmel Cancer Center, San Diego, California 92121, USA.
Bost
Frédéric
F
Charbono
Wilfried
W
Dean
Nicholas
N
McKay
Robert
R
Rhim
Johng S
JS
Depatie
Chantal
C
Mercola
Dan
D
D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020033:Protein Isoforms; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases