Mechanisms of acquired androgen independence during arsenic-induced malignant transformation of human prostate epithelial cells.
BACKGROUND
Prostate cancer progression often occurs with overexpression of growth factors and receptors, many of which engage the Ras/mitogen-activated protein MAP kinase (MAPK) pathway.


OBJECTIVE
In this study we used arsenic-transformed human prostate epithelial cells, which also show androgen-independent growth, to study the possibility that chronic activation of Ras/MAPK signaling may contribute to arsenic-induced prostate cancer progression.


METHODS
Control and chronic arsenic-transformed prostate epithelial cells (CAsE-PE) were compared for Ras/MAPK signaling capacities using reverse transcription-polymerase chain reaction and Western blot analyses.


RESULTS
We found activation of HER-2/neu oncogene in transformed CAsE-PE cells, providing molecular evidence of androgen independence in the transformed cells. CAsE-PE cells displayed constitutively increased expression of unmutated K-Ras (6-fold), and the downstream MAP kinases A-Raf and B-Raf (2.2-fold and 3.2-fold, respectively). There was also increased expression of phosphorylated MEK1/2 and Elk1 in the transformant cells. The MEK1/2 inhibitor, U0126, blocked PSA overexpression in CAsE-PE cells.


CONCLUSIONS
Thus, arsenic-induced malignant transformation and acquired androgen independence are linked to Ras signaling activation in human prostate epithelial cells. Chronic activation of this pathway can sensitize the androgen receptor to subphysiologic levels of androgen. This may be important in arsenic carcinogenesis and provide a mechanism that may be common for prostate cancer progression driven by diverse agents.
Benbrahim-Tallaa
Lamia
L
Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Webber
Mukta M
MM
Waalkes
Michael P
MP
D000728:Androgens / Q000502:physiology; D001151:Arsenic / Q000633:toxicity*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008954:Models, Biological; D011467:Prostate / Q000166:cytology / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000209:etiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048490:raf Kinases / Q000378:metabolism
D000728:Androgens; D001151:Arsenic; D004785:Environmental Pollutants; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D048490:raf Kinases; C410798:AR protein, human