TGF-Beta Antibody for Prostate Cancer: Role of ERK
Annual rept. 15 Jun 2011 - 14 Jun 2012
NORTHWESTERN UNIV EVANSTON IL
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Characteristics of aggressive prostate cancers CaP include a loss of sensitivity to physiologic levels of TGF-Beta due to in part TGF-Beta receptors TBetaRs methylation mediated by DNA methyltransferase DNMT. However, the mechanisms underlying these alterations remain undetermined. We used human CaP cell lines with varying degrees of invasive capability, and human CaP samples to elucidate the mechanisms associated with TGF-Beta insensitivity and disease outcome following radical prostatectomy. We determined that more aggressive CaP cells had significantly higher TGF-Beta levels and increased expression of outcome following radical prostatectomy. We determined that more aggressive CaP cells had significantly higher TGF-Beta levels and increased expression of cells. Blockade of TGF-Beta signaling or the extracellular signal-regulated kinases ERK was associated with a dramatic decrease in the expression of DNMTs, and with a coincident increase in the expression of TBetaRs in cancer cells. In addition, there was a time dependent positive correlation between treatment of cells with TGF-Beta and the expression of p-ERK in CaP cells. In contrast, benign prostate cells demonstrated a negative correlation between TGF-Beta treatment and p-ERK expression. Inhibition of TGF-Beta in an in vivo xenograft model using 1D11 was associated with inhibition of tumor growth but also the downregulation of p-ERK and DNMTs. Finally, independent of Gleason grade, TGF-Beta induced expression of DNMT1 was associated with biochemical recurrence following radical prostatectomy. Our findings demonstrated that CaP tumor derived TGF-Beta may induce expression of DNMTs which subsequently results in the hypermethylation of its own receptors and insensitivity to growth inhibition. ERK activation mediates this feedback loop which is associated with the aggressive potential of CaP.
- Medicine and Medical Research