Activation of Rac1 is closely related to androgen-independent cell proliferation of prostate cancer cells both in vitro and in vivo.
We and others previously showed that signaling through cSrc or atypical protein kinase C (aPKC) pathway regulates the proliferation of prostate cancer cells and is associated with their progression to castrate-resistance in vivo. However, the interrelation of these two kinases has been largely unexplored. In the present study, we show that androgen-induced activation of cSrc regulates the activity of aPKC through the small molecular weight G protein Rac1 in androgen-dependent LNCaP cells. Knockdown of cSrc in those cells reduces the phosphorylation of aPKC and the abundance of activated form of Rac1. Additionally, the treatment of those cells with Rac1 inhibitor repressed cell cycle progression at G(1)/S transition. In fact, forced expression of a constitutively active Rac1 mutant in LNCaP cells promoted cell proliferation under androgen-depleted conditions both in vitro and in vivo. Moreover, LNCaP C4-2 and AILNCaP cells, the syngeneic androgen-independent sublines from LNCaP cells, harbored abundant Rac1-GTP. Importantly, the inhibition of Rac1 suppressed cell proliferation and induced apoptotic cell death in all prostate cancer cell lines tested irrespective of their androgen-dependence. In immunohistochemical evaluation of tumor specimens from prostate cancer patients, Rac1 pathway appeared to be activated in the majority of castrate-resistant diseases. Collectively, our present results both in vitro and in vivo highly implicate that Rac1 can be a potential therapeutic target for patients with advanced prostate cancer, especially those with castrate-resistant status.
Kobayashi
Takashi
T
Department of Urology, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
Inoue
Takahiro
T
Shimizu
Yosuke
Y
Terada
Naoki
N
Maeno
Atsushi
A
Kajita
Yoichiro
Y
Yamasaki
Toshinari
T
Kamba
Tomomi
T
Toda
Yoshinobu
Y
Mikami
Yoshiki
Y
Yamada
Tomomi
T
Kamoto
Toshiyuki
T
Ogawa
Osamu
O
Nakamura
Eijiro
E
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002369:Castration; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D011493:Protein Kinase C / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000728:Androgens; D015741:Metribolone; D016392:Proto-Oncogene Proteins pp60(c-src); C115015:PKC-3 protein; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein