Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β-catenin signaling in prostate cancer cells.
Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naïve PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and β-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and β-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.
Istituto Nazionale per la Ricerca sul Cancro, Largo R Benzi 10, 16132 Genova, Italy.
Monica
M
Ciarlo
Roberto
R
Benelli
Ottavia
O
Barbieri
Simona
S
Minghelli
Paola
P
Barboro
Cecilia
C
Balbi
Nicoletta
N
Ferrari
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055099:Neuroendocrine Cells / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
C410798:AR protein, human; D000728:Androgens; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D011944:Receptors, Androgen; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt