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.
Highlights
Indicated that UA treatment induced apoptosis and increased JNK activation in K562 cells[24]
Further analysis revealed that treatment with 30 μMUA for varying intervals resulted in a time-dependent down-regulation of Mcl-1 and p-Bad at Ser[136], notable change being at 6 hr (Fig. 1b)
We found that UA stimulated the expression of Gfi-1 and decreased Stat5a/b and Akt1/2 expression at transcriptional level in K562 cells
Summary
Indicated that UA treatment induced apoptosis and increased JNK activation in K562 cells[24]. A recent publication described that UA treatment caused inactivation of the PI3K/Akt pathway by increasing PTEN gene expression in K562 cells[25]. The precise molecular mechanisms underlying UA sensitivity to growth inhibition of K562 cells as well as apoptosis induction remain in a large part unclear. We demonstrate that UA induces apoptosis in K562 cells via Stat[5] signaling, overcomes Imatinib resistance, and enhances both K562 and Imatinib-resistant K562/G01 cytotoxicity of Imatinib
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