Friend or foe: role of E-cadherin in prostate cancer metastasis

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. Alteration of E-cadherin protein level during epithelialmesenchymal transition (EMT) or mesenchymal-epithelial transition (MET) plays important role in cancer metastasis (1). In a recent paper “Liver Protects Metastatic Prostate Cancer From Induced Death by Activating E-cadherin Signaling” by Ma et al. (2) reported that the interaction between liver cells and metastatic prostate cancer (PCa) cells provokes re-expression of E-cadherin in PCa cells, which protects PCa cells from cell death induced by chemotherapeutic drugs. E-cadherin fabricates this protection via activation of canonical survival signaling pathways, including the extracellular signal-regulated kinases (ERK), protein kinase B (AKT), and the Janus kinase (JAK) signaling. Ma et al. used DU-145, an androgen-receptor (AR)-negative androgen-independent PCa cell line which expresses very low level of E-cadherin on the cell membrane to determine the role of E-cadherin in PCa chemotherapy resistance. The researchers found that either co-culture with primary hepatocytes to mimic liver cell microenvironment or addition of PD153035 (inhibitor suppressing the kinase activity of epidermal growth factor receptor, EGFR) induced the re-expression of E-cadherin in DU-145. These E-cadherin-high DU-145 cells were much more resistant to chemotherapeutic drugs treatment and TNF-related apoptosis-inducing ligand (TRAIL) both in vitro and in vivo. The finding that elevation of E-cadherin in metastasized DU-145 PCa cells protects PCa cells from chemotherapy is very interesting and may stimulate novel therapies for advanced PCa targeting E-cadherin. However, the difference in AR expression level and phosphatase and tensin homolog (PTEN) status may complicate the effect of E-cadherin on PCa metastasis. In PCa cells, AR modulates the expression of proteins regulating cell cycle, survival and growth. Increase in AR mRNA and protein is observed in castration-resistant prostate cancer (CRPC) as compared to the primary prostate tumors (3). Ligand-activated AR has been reported to bind E-cadherin promoter, to downregulate E-cadherin expression, to activate Snail, to induce EMT, and thus promotes cancer metastasis (4,5). Re-expression of AR in PC-3 cells, another AR-negative PCa cells, increases E-cadherin but represses EMT, migration, and invasion of PC-3 cells in the absence of androgen (6). PTEN is a negative regulator for phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. Deletion of PTEN was observed in 40–70% of PCa patients, resulting in upregulation of PI3K-Akt signaling. Deletion or mutation of PTEN is associated with poor prognosis, cancer metastasis, and progression towards castrationresistant status or PCa (7,8). DU-145 is an AR-negative PCa cell line expressing wild type PTEN. Whether the phenomenon observed in DU-145 is the general case for all PCa cells requires further investigation. It is a good idea to use both LNCaP (AR-positive, mutant PTEN) and PC-3 (AR-negative, PTEN null) for validation. Ma et al. pointed out that E-cadherin promotes protection against chemotherapy drugs partially via activation of Akt1 and Akt2. As Akt3 has been reported to play important role in PCa (9), it will be worthy to examine if Akt3 is involved in Commentary