c-Jun NH2-terminal kinase mediates leptin-stimulated androgen-independent prostate cancer cell proliferation via signal transducer and activator of transcription 3 and Akt

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1782

Article

Miyazaki, Toshiaki^1,2  Bub, Jeffrey D.²  Iwamoto, Yoshiki^1,2 

[1] Beckman Res Inst City Hope, Dept Surg Res, Duarte, CA 91010 USA

[2] Med Coll Wisconsin, Dept Urol, Human & Mol Genet Ctr, Milwaukee, WI 53226 USA

关键词: Prostate cancer;    Obesity;    Leptin;    JNK;    STAT3;    Akt;   

DOI  :  10.1016/j.bbadis.2008.07.005

来源: Elsevier

【 摘 要 】

Obesity is associated with advanced prostate cancer. Here we demonstrate that in mouse prostate cancer TRAMP-Cl cells epididymal fat extracts from high-fat diet-fed obese mice stimulate androgen-independent cell growth more significantly than those from low-fat diet-fed lean mice or genetically obese leptin-deficient ob/ob mice in correlation with leptin concentrations. This result suggests that obesity promotes androgen-independent prostate cancer cell growth via adipose leptin. We have reported that added leptin stimulates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase (JNK). As with JNK, signal transducer and activator of transcription 3 (STAT3) and Akt are implicated in androgen-independent prostate cancer. In this study, we identify novel interaction of these three molecules in leptin-stimulated androgen-independent cell proliferation. Leptin activates JNK. STAT3 and Akt in a biphasic manner with a similar time-course. Pharmacological JNK inhibition suppresses leptin-stimulated DNA binding activity, as well as Ser-727 phosphorylation, of STAT3. Since JNK upregulates STAT3 activity via Set-727 phosphorylation, JNK mediates leptin-stimulated STAT3 activation through Ser-727 phosphorylation. Moreover, JNK inhibition impairs leptin-stimulated Ser-473 phosphorylation of Akt that is required for its activation. Thus, JNK is involved in leptin-stimulated Akt activation. These findings together indicate that JNK mediates leptin-stimulated androgen-independent prostate cancer cell proliferation via STAT3 and Akt. (C) 2008 Elsevier B.V. All rights reserved.

【 授权许可】

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