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Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines

Paola Palozza1, Maria Colangelo, Rossella Simone

  • 1Institute of General Pathology, Catholic University School of Medicine, L. Go F. Vito, 00168 Rome, Italy. p.palozza@rm.unicatt.it

Carcinogenesis
|August 12, 2010
PubMed

Insights

Tomato lycopene inhibits cancer cell growth by reducing cholesterol synthesis and inactivating Ras proteins. This mechanism, observed in prostate and other cancers, involves blocking key signaling pathways and inducing apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Nutritional Science

Background:

  • Cancer cells exhibit dysregulated cholesterol biosynthesis and prenylation of small GTPase proteins.
  • Tomato lycopene shows potential anticancer effects, particularly in prostate cancer, but its molecular mechanisms remain unclear.

Purpose of the Study:

  • To investigate if lycopene's antitumor effects are mediated by alterations in the mevalonate pathway and Ras activation.
  • To elucidate the molecular pathways through which lycopene exerts its growth-inhibitory effects in cancer cells.

Main Methods:

  • Incubation of prostate cancer LNCaP cells with lycopene (2.5-10 μM) for 24 hours.
  • Assessed intracellular cholesterol, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase expression, Ras activation (membrane translocation), and downstream signaling pathways (NF-κB, MAPKs, AKT).
  • Evaluated cell cycle progression, apoptosis markers (cyclin D1, p21, p27, p53, Bax:Bcl-2 ratio), and effects of mevalonate supplementation.

Main Results:

  • Lycopene dose-dependently reduced intracellular cholesterol by decreasing HMG-CoA reductase expression and inactivated Ras.
  • Lycopene inhibited Ras-dependent nuclear factor-kappaB (NF-κB) activation, reactive oxygen species production, and phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase 1/2, and p38.
  • Cell cycle arrest and apoptosis were induced, evidenced by altered levels of cell cycle regulators and apoptosis markers. Mevalonate addition reversed lycopene's effects.
  • Similar inhibitory effects on HMG-CoA reductase, cell growth, and Ras inactivation were observed in prostate (PC-3), colon (HCT-116, HT-29), and lung (BEN) cancer cells.

Conclusions:

  • Lycopene exhibits antitumor properties by modulating the mevalonate pathway and inhibiting Ras activation.
  • These findings offer a novel mechanistic understanding of lycopene's anticancer effects, supporting its potential role in cancer prevention and therapy.
  • Lycopene's ability to inhibit cholesterol synthesis and key signaling pathways presents a promising therapeutic strategy for various cancers.

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