Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor.
It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.
Malinowska
Kamilla
K
Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Neuwirt
Hannes
H
Cavarretta
Ilaria T
IT
Bektic
Jasmin
J
Steiner
Hannes
H
Dietrich
Hermann
H
Moser
Patrizia L
PL
Fuchs
Dietmar
D
Hobisch
Alfred
A
Culig
Zoran
Z
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology; D009919:Orchiectomy; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014105:Tosyl Compounds / Q000494:pharmacology
D000813:Anilides; D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014105:Tosyl Compounds; C053541:bicalutamide; D020928:Mitogen-Activated Protein Kinases