The prostate specific membrane antigen regulates the expression of IL-6 and CCL5 in prostate tumour cells by activating the MAPK pathways.
The interleukin-6 (IL-6) and the chemokine CCL5 are implicated in the development and progression of several forms of tumours including that of the prostate. The expression of the prostate specific membrane antigen (PSMA) is augmented in high-grade and metastatic tumors. Observations of the clinical behaviour of prostate tumors suggest that the increased secretion of IL-6 and CCL5 and the higher expression of PSMA may be correlated. We hypothesized that PSMA could be endowed with signalling properties and that its stimulation might impact on the regulation of the gene expression of IL-6 and CCL5. We herein demonstrate that the cross-linking of cell surface PSMA with specific antibodies activates the small GTPases RAS and RAC1 and the MAPKs p38 and ERK1/2 in prostate carcinoma LNCaP cells. As downstream effects of the PSMA-fostered RAS-RAC1-MAPK pathway activation we observed a strong induction of NF-kappaB activation associated with an increased expression of IL-6 and CCL5 genes. Pharmacological blockade with specific inhibitors revealed that both p38 and ERK1/2 participate in the phenomenon, although a major role exerted by p38 was evident. Finally we demonstrate that IL-6 and CCL5 enhanced the proliferative potential of LNCaP cells synergistically and in a dose-dependent manner and that CCL5 functioned by receptor-mediated activation of the STAT5-Cyclin D1 pro-proliferative pathway. The novel functions attributable to PSMA which are described in the present report may have profound influence on the survival and proliferation of prostate tumor cells, accounting for the observation that PSMA overexpression in prostate cancer patients is related to a worse prognosis.
Colombatti
Marco
M
Department of Pathology, University of Verona, Verona, Italy.
Grasso
Silvia
S
Porzia
Alessandra
A
Fracasso
Giulio
G
Scupoli
Maria Teresa
MT
Cingarlini
Sara
S
Poffe
Ornella
O
Naim
Hassan Y
HY
Heine
Martin
M
Tridente
Giuseppe
G
Mainiero
Fabrizio
F
Ramarli
Dunia
D
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000378:metabolism
D018946:Chemokine CCL5; D015850:Interleukin-6; D016328:NF-kappa B; D050799:STAT5 Transcription Factor; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases; D017430:Prostate-Specific Antigen; D020558:GTP Phosphohydrolases