Osteoblasts induce prostate cancer proliferation and PSA expression through interleukin-6-mediated activation of the androgen receptor.
Prostate cancer (CaP) metastases selectively develop in bone as opposed to other sites through unknown mechanisms. Interleukin-6 (IL-6) is considered to contribute to CaP progression and is produced at high levels in osteoblasts. We hypothesized that osteoblast-derived IL-6 in the bone microenvironment contributes to the fertile soil for CaP growth. Accordingly, human CaP cells, LNCaP, C4-2B and VCaP, were treated with conditioned medium (CM) collected from human osteoblast-like HOBIT cells grown in androgen-depleted medium. We found that CM induced proliferation, prostate-specific antigen (PSA) protein and mRNA expression in a dose-dependent manner in these cell lines as determined by ELISA and real-time PCR, respectively. CM also activated the PSA promoter in these cells. Both HOBIT and primary osteoblast (POB) cells produced high levels of IL-6 measured by bioassay. LNCaP, C4-2B and VCaP cells expressed IL-6, but at much lower levels then the HOBIT and POB and they also expressed the IL-6 receptor mRNA, indicating they can respond to IL-6. Anti-IL-6 antibody added to HOBIT or POB CM dose-dependently inhibited the CM-induced cell proliferation and PSA expression in these CaP cell lines. HOBIT CM induced nuclear translocation of the AR and this was inhibited by anti-IL-6 antibody. Additionally, the antiandrogen bicalutamide inhibited HOBIT CM-induced cell proliferation. These results demonstrate that osteoblasts promote CaP growth through IL-6-mediated activation of the AR. Furthermore, these data underscore the importance of cross-talk between tumor and the bone microenvironment in the development of CaP bone metastases.
Lu
Yi
Y
Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
Zhang
Jian
J
Dai
Jinlu
J
Dehne
Lindsay A
LA
Mizokami
Atsushi
A
Yao
Zhi
Z
Keller
Evan T
ET
D000728:Androgens / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010006:Osteoblasts / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000728:Androgens; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D012333:RNA, Messenger; D011944:Receptors, Androgen; D019947:Receptors, Interleukin-6; D017430:Prostate-Specific Antigen