Differential Androgen Deprivation Therapies with Anti-androgens Casodex/Bicalutamide or MDV3100/Enzalutamide versus Anti-androgen Receptor ASC-J9® Lead to Promotion versus Suppression of Prostate Cancer Metastasis

Abstract

Background: Androgen deprivation therapy (ADT) suppresses prostate cancer (PCa) growth, yet its effects on PCa metastasis remain unclear. Results: ADT with MDV3100/enzalutamide or Casodex/bicalutamide versus ASC-J9 led to enhanced versus suppressed PCa metastasis. Conclusion: Casodex/MDV3100 induces PCa metastasis via modulation of TGF-␤1/Smad3/MMP9 signaling. Significance: Targeting androgen receptor with ASC-J9 is better than targeting androgens with Casodex/MDV3100 to better battle PCa metastasis.

Inhibition of Protein Kinase C/Twist1 Signaling Augments Anticancer Effects of Androgen Deprivation and Enzalutamide in Prostate Cancer

“…1C), PKC phosphorylation, and Twist1 protein expression, which was accompanied by a decreased E-cadherin and an increased fibronectin expression (Fig. 1D), consistently with the previous reports on EMT promotion by enzalutamide (27,28).…”

Androgen Receptor Splice Variant AR3 Promotes Prostate Cancer via Modulating Expression of Autocrine/Paracrine Factors

“…This notion is supported by previous studies that 22Rv1 cells are less dependent on AR, and the truncated AR isoforms can drive castrationresistant growth in these cells when AR is knocked down (59,60). Interestingly, a recent study showed that the anti-androgens targeting the AR ligand binding domain promotes tumor metastasis via increasing TGF␤ expression whereas the anti-AR N-terminal drug ASC-J9 inhibits tumor metastasis (61). ASC-J9 has been shown to inhibit AR3 activity in a number of prostate cancer cells (59).…”

WITHDRAWN: Mechanisms navigating the TGF-β pathway in prostate cancer

“…Such metastasis-blocking effects are reversed by TGF-b-induced EMT, indicating a crosstalk between EMT effectors and MMP-9 in prostate tumor progression to metastasis. Moreover, clinically used first and second generation anti-androgens, Casodex or MDV3100 (enzalutamide), suppress prostate cancer cell growth yet promote prostate cancer cell invasion by activating the TGF-b1/ SMAD3/MMP9 pathway [55]. A newly developed anti-AR compound, ASC-J9, produces anti-invasion effects against prostate cancer by down-regulating MMP9 expression [55].…”

“…Moreover, clinically used first and second generation anti-androgens, Casodex or MDV3100 (enzalutamide), suppress prostate cancer cell growth yet promote prostate cancer cell invasion by activating the TGF-b1/ SMAD3/MMP9 pathway [55]. A newly developed anti-AR compound, ASC-J9, produces anti-invasion effects against prostate cancer by down-regulating MMP9 expression [55]. Endothelial cell-induced prostate cancer invasion can be functionally prevented by blocking the IL-6/AR/TGF-b/ MMP-9 signaling pathway [56].…”