No abstract

Several evidences suggest that cancer cells have abnormal cholesterol biosynthetic pathways and prenylation of small guanosine triphosphatase proteins. Tomato lycopene has been suggested to have beneficial effects against certain types of cancer, including that of prostate, although the exact molecular mechanism(s) is unknown. We tested the hypothesis that lycopene may exert its antitumor effects through changes in mevalonate pathway and in Ras activation. Incubation of the Ras-activated prostatic carcinoma LNCaP cells with a 24 h lycopene treatment (2.5-10 μM) dose dependently reduced intracellular total cholesterol by decreasing 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase expression and by inactivating Ras, as evidenced by its translocation from cell membranes to cytosol. Concomitantly, lycopene reduced the Ras-dependent activation of nuclear factor-kappaB (NF-κB). Such a reduction was parallel to an inhibition of reactive oxygen species production and to a decrease in the phosphorylation ofc-jun N-terminal kinase, extracellular signal-regulated kinase 1/2 and p38. These effects were also accompanied by an arrest of cell cycle progression and by apoptosis induction, as evidenced by a decrease in cyclin D1 and phospho-AKT levels and by an increase in p21, p27 and p53 levels and in Bax:Bcl-2 ratio. The addition of mevalonate prevented the growth-inhibitory effects of lycopene as well as its increase in Ras cytoplasmatic accumulation and the subsequent changes in NF-κB. The ability of lycopene in inhibiting HMG-CoA reductase expression and cell growth and in inactivating Ras was also found in prostate PC-3, colon HCT-116 and HT-29 and lung BEN cancer cells. These findings provide a novel mechanistic insight into the growth-inhibitory effects of lycopene in cancer.

Background/Aims: Increased ingestion of tomato, containing lycopene, has been associated with a decreased risk for atherosclerosis, although the exact molecular mechanism is still unknown. Here we review the available evidence for a direct regulation of tomato lycopene on cholesterol metabolism using results from experimental and human studies. Results: In human macrophages lycopene dose dependently reduced intracellular total cholesterol. Such an effect was associated with a decrease in cholesterol synthesis through a reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and expression, a modulation of low- density lipoprotein (LDL) receptor and acyl-coenzyme A:cholesterol acyltransferase activity. An increase in cholesterol efflux through an enhancement of ABCA1 and caveolin-1 expression was also observed. In animal models of atherosclerosis, lycopene and tomato products decreased plasma total cholesterol, LDL cholesterol and increased high-density lipoprotein cholesterol. In agreement with the experimental results, most human intervention trials analyzed show that dietary supplementation with lycopene and/or tomato products reduced plasma LDL cholesterol dependently on the dose and the time of administration. Conclusions: Although lycopene and tomato products seem to possess direct hypocholesterolemic properties, more experimental studies are needed to better understand the mechanisms involved. There is also a need for more well-designed human dietary intervention studies to better clarify the role of lycopene as a hypocholesterolemic agent.

No abstract

No abstract