The existence of a crosstalk between the androgen receptor (AR) pathway
and interleukin-6 (IL-6) signaling in prostate cancer (PCa) is broadly recognized. IL-6
activates the AR in a ligand-independent manner leading to the transcription of prostatespecific
antigen (PSA), the most widely used marker for the detection and monitoring of
PCa. IL-6 expression is increased in the malignant epithelium of prostate cancer
patients and its levels are enhanced in the plasma of patients with late-stage disease.
Interestingly, IL-6 is able to shift from being a paracrine growth inhibitor to an
autocrine growth stimulator in PCa cells. Hence, IL-6 has been implicated in the
progression towards castration-resistant prostate cancer (CRPC), in which elevated
levels are indicative of poor prognosis and predict resistance to chemotherapy with
taxanes. We will depict here the IL-6 signaling pathway and its contribution to PCa. For
this purpose, we will portray the molecular events that prompted the origin of LNCaPIL-
6+ cells, a model of advanced PCa, upon chronic exposure to IL-6. We will also
examine the similarities between LNCaP-IL-6+ cells and late-stage prostatic carcinoma.
In addition, we will reveal the effect of CNTO 328, a chimeric monoclonal antibody
targeting IL-6, in LNCaP-IL-6+ cells, as well as discuss the latest results from clinical
trials with CNTO 328 in CRPC patients. Finally, we will speculate on the possibility,
not yet investigated, of administering CNTO 328 to patients before the onset of CRPC.
Keywords: Interleukin-6 (IL-6), prostate cancer, castration-resistant prostate
cancer, androgen deprivation therapy, androgen receptor, androgen, antiandrogen,
JAK/STAT, MAP kinase, VEGF, retinoblastoma, clinical trials, prostate specific
antigen (PSA).
