Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer.
BACKGROUND
Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells.


RESULTS
In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens.


CONCLUSIONS
Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8.
Gannon
Philippe O
PO
Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal, Montreal, Quebec, Canada.
Godin-Ethier
Jessica
J
Hassler
Matthew
M
Delvoye
Nathalie
N
Aversa
Meghan
M
Poisson
Alexis O
AO
Péant
Benjamin
B
Alam Fahmy
Mona
M
Saad
Fred
F
Lapointe
Réjean
R
Mes-Masson
Anne-Marie
AM
D000728:Androgens / Q000378:metabolism*; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007108:Immune Tolerance; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011944:Receptors, Androgen / Q000378:metabolism
D000728:Androgens; D016209:Interleukin-8; D011944:Receptors, Androgen; D001119:Arginase