EGF promotes neuroendocrine-like differentiation of prostate cancer cells in the presence of LY294002 through increased ErbB2 expression independent of the phosphatidylinositol 3-kinase-AKT pathway

Abstract

An increased neuroendocrine (NE) cell population in prostate cancer is associated with more aggressive disease and recurrence after androgen-deprivation therapy, although the mechanism responsible is unknown. In this study, we report that the treatment of LNCaP cells with epidermal growth factor (EGF) in the presence of LY294002, an inhibitor of the phosphoinositol 3'-kinase (PI3K)-AKT pathway, induced an increase of levels and activity of ErbB2. Under these conditions, we also observed cell survival and NE differentiation. When we treated with wortmannin, another PI3K inhibitor, or we knocked down PI3K or AKT isoforms in the presence of EGF, ErbB2 up-regulation was not observed, suggesting that the increase of ErbB2 induced by EGF plus LY294002 is not mediated by the PI3K-Akt pathway. Other targets of LY294002 were also discounted. We also show that ErbB2 up-regulation is directly involved in neuroendocine differentiation but not in cell survival as ErbB2 levels increased in parallel with NE differentiation marker levels, whereas ErbB2 knockdown reduced them; other NE differentiation inducers also increased the ErbB2 levels and the immunohistochemical analysis of prostate cancer samples showed colocalization of ErbB2 and chromogranin A. We found that, in LNCaP cells, EGF in combination with LY294002 increased ErbB2 levels by a PI3K/AKT-independent mechanism and that this increase was associated with the acquisition of a NE phenotype. These results suggest that is worth reconsidering ErbB2 as a drug target in prostate cancer and this should be kept in mind when designing new clinical schedules for the treatment of this disease.

Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications

“…EGFR has been shown to signal through various pathways including the MAPK-pathway [40], and EGF treatment has been demonstrated to promote neuroendocrine-like state in LNCaP cells [41]. Taken together, this adds support to role of the MAPK pathway seen previously (Figure 6) in the NED process.…”

TPD52 represents a survival factor inERBB2‐amplified breast cancer cells

“…Transient TPD52 isoform knock‐down also produced increased cell death in LnCaP prostate cancer cells , and in the androgen‐independent derivative cell line C4‐2 . As both LnCaP and C4‐2 cells express ERBB2 the consequences of TPD52 knock‐down in these cell lines are consistent with TPD52 promoting the survival of ERBB2‐positive cancer cells. However, Kourtidis et al also reported that the ERBB2‐negative breast cancer cell line MDA‐MB‐468 showed similar reductions in viability to TPD52 knock‐down as ERBB2 ‐amplified and/or ‐expressing cell lines.…”

Anti‐androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation via altering the infiltrated mast cells → androgen receptor (AR) → miRNA32 signals

“…Alonzeau J et al. found 26RFa might participate in the development of PCa via promoting the PCa NE differentiation (Alonzeau et al., 2013), and IL‐6, EGF or Wnt‐11 could induce NE‐like differentiation in LNCaP cells (Qiu et al., 1998,Cortés et al., 2012).…”