Abstract
Cancer metastasis is a major cause of death for cancer patients, so effectively inhibited the metastasis of cancer cells can be used as one of the therapeutic strategies. alpha-Carotene is one of major carotenoids in human plasma, and is found in dark green and orange fruits and vegetables such as carrots, pumpkin, spinach and tomato. alpha-Carotene has been shown to possess anti-cancer activity both in vitro and in vivo. Epidemiological studies have indicated that elevated serum alpha-carotene concentration is associated with reduced risks of several types of chronic diseases including cancer. In addition, beta-carotene, similar structure of alpha-carotene, has been found to exhibits anti-metastatic effects both in vitro and in vivo. However, little is known whether alpha-carotene exerts anti-metastatic effects on human hepatocarcinoma cells. In the first part of this study, we investigated the anti-metastatic effects of alpha-carotene in comparison with beta-carotene in human hepatocarcinoma SK-Hep-1 cells. We found that both alpha-carotene and beta-carotene significantly inhibited the cell invasion, migration and adhesion and that the effects of alpha-carotene were concentration dependent. Mechanistically, alpha-carotene: (1) inhibited the activities of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator (uPA); (2) increased the protein expression of nm23-H1, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of MMP (TIMP)-1 and -2; (3) inhibited the protein expression of Rho small GTPase (Rho and Rac 1); and (4) decreased focal adhesion kinase (FAK)-mediated signaling pathway, such as mitogen-activated protein kinases (MAPKs) family protein. Overall, the results demonstrate that alpha-carotene significantly inhibits the metastasis of SK-Hep-1 cells, and that this effect is stronger than beta-carotene at the same concentration. Carotenoids are widely distributed in plant foods and fruits. The hydrocarbon carotenoids, alpha-carotene, beta-carotene and lycopene, the monohydroxy xanthophylls, beta-cryptoxanthin, and the dihydroxy xanthophylls, lutein, are the main carotenoids present in human plasma and tissues. Epidemiological studies have found that serum total carotenoids show interaction effects on mortality and further reduce the risk of cancer. However, little is known whether multi-carotenoids exert anti-metastatic effects in cancer cells. In the second part of this study, we chose different physiological concentrations of alpha-carotene, beta-carotene, lycopene, lutein and beta-cryptoxanthin in the serum of Taiwanese and American to investigate whether theses combination protects against metastasis in human hepatocarcinoma SK-Hep-1 cells. Results show that both multi-carotenoids mixture of Taiwanese (MCT) and American (MCA) significantly inhibit SK-Hep-1 cells metastasis and display an additive effect. We also found that the mechanism of anti-metastasis were: (1) decreased the activities of matrix metalloproteinase (MMP)-2, 9 and increased the protein expression of tissue inhibitor of MMP, (TIMP)-1, 2 result in inhibiting cells invasion; and (2) reduced the protein expression of Rho and Rac 1 to inhibit cells migration or adhesion. In addition, our results suggest that anti-metastatic efficacy of MCA is stronger than that of MCT because the total concentration of MCA (1.8 microM) is higher than MCT (1.4 nicroM). In summary, this dissertation research demonstrates that (1) alpha-carotene posses anti-metastatic activity; (2) combination with physiological concentrations of carotenoids could be anti-metastasis with an additive effect. Overall, we conclude that carotenoids, either alone or in combination, might be apply for anti-metastasis.
Published Version
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