title: Ursolic acid-mediated apoptosis of K562 cells involves Stat5/Akt pathway inhibition through the induction of Gfi-1.
abstract: Ursolic acid (UA) is a promising natural compound for cancer prevention and therapy. We previously reported that UA induced apoptosis in CML-derived K562 cells. Here we show that the apoptotic process is accompanied by down-regulation of Bcl-xL and Mcl-1 expression and dephosphorylation of Bad. These events are associated with Stat5 inhibition, which is partially mediated through elevated expression of transcriptional repressor Gfi-1. Gfi-1 knockdown using siRNA abrogates the ability of UA to decrease Stat5b expression and attenuates apoptosis induction by UA. We also demonstrate that UA suppresses the Akt kinase activity by inhibiting Akt1/2 expression, which correlates with Stat5 inhibition. Stat5 activity inhibited by a chemical inhibitor or siRNA, Akt1/2 mRNA expression is suppressed. Moreover, we show that UA exerts growth-inhibition in Imatinib-resistant K562/G01. UA has synergistic effects when used in combination with Imatinib in both K562 and K562/G01. Altogether, the data provide evidence that UA's pro-apoptotic effect in K562 cells is associated with the Gfi-1/Stat5/Akt pathway. The findings indicate that UA could potentially be a useful agent in the treatment of CML.
authors.affiliation: Department of Biochemistry, Shantou University Medical College, No. 22 Xinlin Road, Jinping District, Shantou, 510451, China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, Shantou University Medical College, No. 22 Xinlin Road, Jinping District, Shantou, 510451, China.
authors.forename: Jikai
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry, Guangzhou Medical University, Xinzao Town, Panyu District, Guangzhou 511436, China.
authors.forename: Xiao-Shan
authors.initials: XS
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D020014:K562 Cells; D008954:Models, Biological; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D004268:DNA-Binding Proteins; D000068877:Imatinib Mesylate; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D014315:Triterpenes; D000097245:Ursolic Acid; C498275:GFI1 protein, human; C494095:STAT5B protein, human