TGF-Beta Antibody for Prostate Cancer: Role of ERK
Abstract
Characteristics of aggressive prostate cancers (CaP) include a loss of sensitivity to physiologic levels of TGF- due to in part TGF- receptors (T Rs) 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 mechanism(s) associated with TGF- insensitivity and disease outcome following radical prostatectomy. We determined that more aggressive CaP cells had significantly higher TGF- levels and increased expression of DNMTs compared to benign and less aggressive prostate cancer cells. In contrast, T Rs expression was significantly reduced in more aggressive cancer cells. Blockade of TGF- 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 T Rs in cancer cells. In addition, there was a time dependent positive correlation between treatment of cells with TGF- and the expression of p-ERK in CaP cells. In contrast, benign prostate cells demonstrated a negative correlation between TGF- treatment and p-ERK expression. Inhibition of TGF- 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- induced expression of DNMT1 was associated with biochemical recurrence following radical prostatectomy. Our findings demonstrated that CaP tumor derived TGF- may induce the 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. In addition, this pathway may have future clinical implications in CaP as a therapeutic target and a prognostic tool.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2011
- Accession Number
- ADA601827
Entities
People
- Chung Lee
Organizations
- Northwestern University