Characterization of Androgen Regulation of ZEB-1 and PSA in 22RV1 Prostate Cancer Cells

Abstract

Two-thirds of patients who present with metastatic prostate cancer (PC) are dead within 5 years of diagnosis. The comparable survival rate for patients with localized disease is 100%, which clearly stresses the need for pursuing and developing bioassays that allow prediction of which localized cases are most likely to metastasize. The commonly assayed prostate specific antigen (PSA), while touted as a transformation biomarker, has recently proven to be problematic in the area of false positive diagnoses. It remains, however, a hallmark gene for studying androgen regulation as its expression is reliably stimulated by androgens such as dihydrotestosterone (DHT). Herein, we have elucidated the effects of flutamide (a defined anti-androgen) and DHT on the expression of PSA and Zinc finger E-box Binding factor (ZEB-1). Additionally, we assayed the androgenic capabilities of two DHT derivatives on expression of PSA. Our previous research had identified ZEB-1 as a putative biomarker for the onset of metastasis in prostate cancer. The expression of this gene is regulated by androgen and decreases sharply at metastasis. In the current study, the effects of 1 and 10 nM flutamide, in combination with 1 and 10 nM DHT, on expression of ZEB-1 and PSA, were investigated in 22Rv1, an androgen-responsive human PC cell line. Also in this cell line, the effects of testosterone propionate and dehydroisoandrosterone were studied. Our research confirmed the feasibility of considering ZEB-1 a metastatic PCa biomarker, using the highly sensitive technique of real-time polymerase chain reaction (RT-PCR). Interestingly, it also revealed the danger of using flutamide as a therapeutic antagonist, as we demonstrate herein its alarming capability to behave as an agonist.

Repression of E-cadherin by SNAIL, ZEB1, and TWIST in invasive ductal carcinomas of the breast: a cooperative effort?

“…More importantly, our data showed that down-regulation of ZEB1 gene expression correlated with poor overall survival (P = .011) and diseasefree survival (P = .053). These results are surprising, because ZEB1 expression has been suggested as a biomarker of metastasis in a prostate cancer cell line and related with androgen regulation [25]. However, it is also possible that our samples represent tumors in which E-cadherin expression is temporarily lost, allowing tumor cells to migrate.…”

Epithelial mesenchymal-like transition occurs in a subset of cells in castration resistant prostate cancer bone metastases

“…Slug and Zeb1 are well-known transcription factors downstream of TGFβ and Twist and there is a plethora of literature relating the role of Slug in EMT, cell proliferation and invasiveness of metastatic PCa cell lines [15, 41, 48]. Zeb1 expression is seen in highly aggressive PCa cells and correlates directly with Gleason grade in human prostate tumors [1]. Additionally, the reversal of the EMT phenotype in PC3 cells has been associated with the down-regulation of ZEB1, ZEB2, and SLUG [11, 12].…”

E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer

“…In human cancers, high ZEB1 expression correlated significantly with a high Gleason score in prostate carcinomas and was suggested as biomarker for metastasis [140,150].…”