Regulation of cell cycle progression and apoptosis by beta-carotene in undifferentiated and differentiated HL-60 leukemia cells: possible involvement of a redox mechanism.
Although epidemiologic studies have demonstrated that a high intake of vegetables containing beta-carotene lowers the risk of cancer, recent intervention studies have revealed that beta-carotene supplementation to smokers resulted in a high incidence of lung cancer. We hypothesized that beta-carotene may act as a pro- or anticancerogenic agent by modulating pathways involved in cell growth and that such a modulation may involve a redox mechanism. To test this hypothesis, cell proliferation, apoptosis and redox status were evaluated in undifferentiated and dimethylsulfoxide-differentiated HL-60 cells exposed to beta-carotene. The carotenoid modified cell cycle progression and induced apoptosis in a dose-dependent manner. These effects were more remarkable in undifferentiated cells than in differentiated cells. In accord with these findings, in undifferentiated cells, beta-carotene was more effective in decreasing cyclin A and Bcl-2 expression and in increasing p21 and p27 expression. Neither Bcl-xL nor Bax expression were significantly modified by the carotenoid. From a mechanistic point of view, the delay in cell growth by beta-carotene was highly coincident with the increased intracellular reactive oxygen species production and oxidized glutathione content induced by the carotenoid. Moreover, alpha-tocopherol minimized the effects of beta-carotene on cell growth. These data provide evidence that beta-carotene modulates molecular pathways involved in cell cycle progression and apoptosis and support the hypothesis that a redox mechanism may be implicated. They also suggest that differentiated cells may be less susceptible to the carotenoid than highly neoplastic undifferentiated cells.
Palozza
Paola
P
Institute of General Pathology, Catholic University, Rome, Italy. ibipg@rm.unicatt.it
Serini
Simona
S
Torsello
Angela
A
Boninsegna
Alma
A
Covacci
Valeria
V
Maggiano
Nicola
N
Ranelletti
Franco O
FO
Wolf
Federica I
FI
Calviello
Gabriella
G
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019803:Glutathione Disulfide / Q000378:metabolism; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019207:beta Carotene / Q000494:pharmacology*
C494826:BAX protein, human; C494811:BCL2L1 protein, human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019207:beta Carotene; D050760:Cyclin-Dependent Kinase Inhibitor p27; D024502:alpha-Tocopherol; D019803:Glutathione Disulfide; D004121:Dimethyl Sulfoxide