Activation of the orphan nuclear receptor RORα counteracts the proliferative effect of fatty acids on prostate cancer cells: Crucial role of 5‐lipoxygenase

Moretti, Roberta M.; Marelli, Marina Montagnani; Sala, Angelo; Motta, Marcella; Limonta, Patrizia

doi:10.1002/ijc.20387

Cited by 47 publications

(37 citation statements)

References 44 publications

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“…Histological analysis of human adenoma samples found that 5-LOX expression was strongly correlated with polyp size and intra-epithelial neoplasia. Consistent with these findings the addition of 5-HETE to breast and prostate cancer cells in vitro enhanced proliferation (Avis et al, 2001;Moretti et al, 2004) and 5-LOX inhibition induced apoptosis in LNCaP and PC3 prostate cancer cells; thus, 5-LOX metabolites maintain tumor cell viability (Ghosh & Myers, 1998). Cell death was prevented by direct addition of 5-HETE and its analogues (Ghosh & Myers, 1998).…”

Section: Lox Metabolites In Tumorigenesissupporting

confidence: 77%

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

Murray

Hraiki

Bebawy

et al. 2015

Pharmacology & Therapeutics

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Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer.

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Section: Lox Metabolites In Tumorigenesissupporting

confidence: 77%

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

Murray

Hraiki

Bebawy

et al. 2015

Pharmacology & Therapeutics

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“…These effects had been observed in tumor cell lines of breast (39), prostate (40) and colon carcinoma (41). Melanoma is an aggressive form of skin cancer associated with high mortality and limited response to therapy once extended beyond the skin (42)(43)(44).…”

Section: Introductionmentioning

confidence: 78%

“…Melatonin nuclear receptors, recently identified in keratinocytes, melanocytes and fibroblasts (18) as well as in hair follicles (28), belong to the retinoid orphan receptor subfamily (RZR/ROR). It was shown that all these human (18,40,59). Here, we tested melatonin for its potential oncostatic effects by assaying for proliferation and colony growth suppression in four different melanoma cell lines (three amelanotic lines including SBCE2, WM-98 and WM-164 derived from vertical and radial growth phases or metastasis, respectively, and SKMEL-188, which can produce melanin pigment).…”

Section: Introductionmentioning

confidence: 99%

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

Fischer

Żmijewski²,

Zbytek³

et al. 2006

Int J Oncol

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Abstract.Melatonin has been shown to have oncostatic effects on malignant melanoma in vitro and in vivo. We studied the growth suppressive effects of melatonin over a wide range of concentrations in four melanoma cell lines (SBCE2, WM-98, WM-164 and SKMEL-188) representative for different growth stages and phenotype. Melanoma cells were incubated with melatonin 10 -12 -10 -3 M, and proliferation and clonogenicity was assessed at 12 h and 14 days, respectively. We also determined the expression of cytosolic quinone oxidoreductases NQO1, NQO2 (known as MT3 receptor) and nuclear receptor ROR· by RT-PCR. Melatonin at pharmacological concentrations (10 -3 -10 -7 M) suppressed proliferation in all melanoma cell lines. In SKMEL-188 cells cultured in serum-free media, melatonin at low concentrations (10 -12 -10 -10 M) also slightly attenuated the proliferation. The effects of pharmacological doses of melatonin were confirmed in the clonogenic assay. Expression of NQO1 was detected in all cell lines, whereas NQO2 and nuclear receptor ROR· including its isoform ROR·4 were present only in SBCE2, WM-164 and WM-98. Thus, melatonin differentially suppressed proliferation in melanoma cell lines of different behaviour. The intensity of the oncostatic response to melatonin could be related to the cell-line specific pattern of melatonin cellular receptors and cytosolic binding protein expression.

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“…Aberrant AA metabolism in tumor cells seems to be dependent on the action of COX-2 and specific LOX (Cuendet & Pezzuto 2000), and these enzymes are over-expressed in PCa in a strict association with tumor grade (Madaan et al 2000). Although different LOXs may exert opposite effects on PCa cells, recent studies have focused on 5-LOX activity as a key regulator of tumor aggressiveness in PCa cell lines (Ghosh & Myers 1998a, Moretti et al 2004, Hassan & Carraway 2006. Moreover, 5-LOX has been considered an attractive target, together with COX-2, in antitumoral therapy, in cancer types possessing a basal high capacity in metabolizing AA, like PCa (Gugliucci et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Arachidonic acid modulates the crosstalk between prostate carcinoma and bone stromal cells

Angelucci

Garofalo²,

Speca³

et al. 2008

Endocrine Related Cancer

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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-a (TGF-a) 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 -a (TGF-a), tumour necrosis factor-a (TNF-a) and interleukin-1 b (IL-1b) 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-a, the number of osteoblasts, and the production of receptor activator for nuclear factor k 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 PCaderived metastatic lesions and indicate new molecular targets for the therapy of metastatic PCa.

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Activation of the orphan nuclear receptor RORα counteracts the proliferative effect of fatty acids on prostate cancer cells: Crucial role of 5‐lipoxygenase

Abstract: The incidence of prostate carcinoma is very low in Eastern countries, such as Japan, suggesting that life style conditions may play a crucial role in the development of this pathology.

Cited by 47 publications

References 44 publications

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

Arachidonic acid modulates the crosstalk between prostate carcinoma and bone stromal cells

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