Constitutive activation of the 41- and 43-kDa mitogen-activated protein (MAP) kinases in the progression of prostate cancer to an androgen-independent state.
OBJECTIVE
The 41- and 43-kDa mitogen-activated protein kinases (MAPK; ERK2 and ERK1, respectively) play pivotal roles in the mitogenic signal transduction pathway. We previously demonstrated that constitutive activation of the MAPK cascade was related to the carcinogenesis of human tumors. In this study, we examined whether constitutive activation of MAPK was related to the progression to androgen independence of prostate cancer.


METHODS
MAPK activation was examined by the appearance of phosphorylated forms and an in vitro kinase assay in four human (androgen-dependent and independent) prostate cancer cell lines and rat prostate cancer cell line Dunning (androgen-sensitive G line, and androgen-independent AT-3, AT-6 sublines). In addition, when androgen-dependent mouse Shionogi Carcinoma 115 (SC115) cells were serially cultured without androgen to obtain androgen-independent cells, the time and degree of MAPK activation were examined.


RESULTS
One of three human androgen-independent cell lines (DU145) showed constitutive activation of MAPK, while an androgen-dependent cell line (LNCaP) did not show MAPK activation. While MAPK were not activated in an androgen-sensitive Dunning G cell line, MAPK were activated in androgen-independent sublines (AT-3 and AT-6) derived from a G cell line. In addition, when SC115 cells were serially cultured without androgen, the cells 16-24 weeks after androgen removal showed MAPK activation. Furthermore, in subcloned cells, MAPK activation was observed even in the cells maintained for 9 weeks in medium without testosterone.


CONCLUSIONS
The present fi ndings suggest that constitutive activation of MAPK may be associated with the acquisition of hormone independence in prostate cancer and that clonal selection after androgen removal and hormone-independent growth through the MAPK signal transduction pathway could begin at a relatively early period in the individual cells.
Oka
Hiroya
H
Department of Urology, Nara Social Insurance Hospital, Nara, Japan. hoka@kcn.ne.jp
Chatani
Yuji
Y
Kohno
Michiaki
M
Kawakita
Mutsushi
M
Ogawa
Osamu
O
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D003470:Culture Media; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000097:blood* / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013739:Testosterone / Q000494:pharmacology*
D000728:Androgens; D014408:Biomarkers, Tumor; D003470:Culture Media; D013739:Testosterone; D020929:Mitogen-Activated Protein Kinase Kinases