Arachidonic acid modulates the crosstalk between prostate carcinoma and bone stromal cells.
Diets high in n-6 fatty acids are associated with an increased risk of bone metastasis from prostate carces (PCa). The molecular mechanism underlying this phenomenon is largely unknown. Arachidonic acid (AA) and its precursor linoleic acid can be metabolized to produce pro-inflammatory cytokines that act as autocrine and paracrine regulators of cancer behavior. We and other authors have previously reported that factors released by PCa cells excite an aberrant response in bone marrow stromal cells (BMSCs). We planned to study how AA may modulate in vitro the interaction between PCa cells and human BMSCs. First, we observed that AA is a potent mitogenic factor for PCa cells through the production of both 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) metabolites. While 5-LOX controls cell survival through the regulation of the Bcl-2/Bax ratio, COX-2 activity stimulates the release of transforming growth factor-alpha (TGF-alpha) and pro-inflammatory cytokines. The blockade of COX-2 activity through a specific inhibitor is sufficient to repress AA-induced gene transcription. The over-expression of transforming growth factor -alpha (TGF-alpha), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) by AA-primed PCa cells resulted particularly effective in modifying cell behavior of cultured human BMSCs. In fact, we observed an increment in the cell number of BMSCs, due prevalently to the action of TGF-alpha, the number of osteoblasts, and the production of receptor activator for nuclear factor kappa B ligand (RANKL), events mainly controlled by inflammatory cytokines. These findings provide a possible molecular mechanism by which dietary n-6 fatty acids accumulating in bone marrow may influence the formation of PCa-derived metastatic lesions and indicate new molecular targets for the therapy of metastatic PCa.
Angelucci
Adriano
A
Department of Basic and Applied Biology, University of L'Aquila, L'Aquila, Italy. adriano.angelucci@gmail.com
Garofalo
Stefania
S
Speca
Silvia
S
Bovadilla
Antonella
A
Gravina
Giovanni Luca
GL
Muzi
Paola
P
Vicentini
Carlo
C
Bologna
Mauro
M
D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology*; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D053583:Interleukin-1beta; D053245:RANK Ligand; D012333:RNA, Messenger; C439524:TNF protein, human; C505688:TNFSF11 protein, human; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2