Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction.
Kaempferol (3,4',5,7-tetrahydroxyflavone) is a flavonoid with anti- and pro-oxidant activity present in various natural sources. Kaempferol has been shown to posses anticancer properties through the induction of the apoptotic program. Here we report that treatment of the chronic myelogenous leukemia cell line K562 and promyelocitic human leukemia U937 with 50 microM kaempferol resulted in an increase of the antioxidant enzymes Mn and Cu/Zn superoxide dismutase (SOD). Kaempferol treatment induced apoptosis by decreasing the expression of Bcl-2 and increasing the expressions of Bax. There were also induction of mitochondrial release of cytochrome c into cytosol and significant activation of caspase-3, and -9 with PARP cleavage. Kaempferol treatment increased the expression and the mitochondria localization of the NAD-dependent deacetylase SIRT3. K562 cells stably overexpressing SIRT3 were more sensitive to kaempferol, whereas SIRT3 silencing did not increase the resistance of K562 cells to kaempferol. Inhibition of PI3K and de-phosphorylation of Akt at Ser473 and Thr308 was also observed after treating both K562 and U937 cells with kaempferol. In conclusion our study shows that the oxidative stress induced by kaempferol in K562 and U937 cell lines causes the inactivation of Akt and the activation of the mitochondrial phase of the apoptotic program with an increase of Bax and SIRT3, decrease of Bcl-2, release of cytochrome c, caspase-3 activation, and cell death.
Marfe
Gabriella
G
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
Tafani
Marco
M
Indelicato
Manuela
M
Sinibaldi-Salimei
Paola
P
Reali
Valentina
V
Pucci
Bruna
B
Fini
Massimo
M
Russo
Matteo Antonio
MA
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D044949:Kaempferols / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D056566:Sirtuin 3; D037761:Sirtuins / Q000187:drug effects / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D044949:Kaempferols; D024101:Mitochondrial Proteins; D051028:bcl-2-Associated X Protein; C006552:kaempferol; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D037761:Sirtuins