Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran.
Medical Laboratory Sciences Program, Division of Health studies, College of Health and Human Sciences, Northern Illinois University, DeKalb, Illinois, USA.
Cell Biol Int. 2022 Jun;46(6):895-906. doi: 10.1002/cbin.11779. Epub 2022 Mar 13.
S-phase kinase-associated protein 2 (Skp2) is a well-defined component of the Skp2-Culin1-F-box (SCF) E3 ubiquitin ligase complex, which is involved in cell cycle progression and considered a prognostic marker in cancers. Overexpression of Skp2 is frequently observed in patients with acute lymphoblastic leukemia (ALL). Inhibition of this protein may be a valuable strategy to induce apoptosis in malignant cells. Less well known is the effect of Skp2 inhibition on the potentiation of the chemotherapeutic-induced cell death in B cell precursor acute lymphoblastic leukemia (BCP-ALL). Our results demonstrated that inhibition of the Skp2 using SZL P1-41, not only resulted in caspase-mediated apoptosis but also potentiated doxorubicin-induced apoptosis in BCP-ALL cell lines (NALM-6 and SUP-B15). SZL P1-41 in combination with doxorubicin altered cell cycle distribution and the level of cyclins and cyclin-dependent kinases in BCP-ALL cells. DNA damage response genes were also upregulated in presence of the doxorubicin and SZL P1-41 in both cell lines. In conclusion, our results indicated that inhibition of Skp2 either alone or in a combination with doxorubicin may hold promise in the future treatment of BCP-ALL.
S 期激酶相关蛋白 2（Skp2）是 Skp2-Culin1-F-box（SCF）E3 泛素连接酶复合物的明确组成部分，该复合物参与细胞周期进程，并被认为是癌症的预后标志物。Skp2 的过表达在急性淋巴细胞白血病（ALL）患者中经常观察到。抑制这种蛋白质可能是诱导恶性细胞凋亡的一种有价值的策略。不太为人所知的是 Skp2 抑制对 B 细胞前体急性淋巴细胞白血病（BCP-ALL）中化疗诱导的细胞死亡增强的影响。我们的结果表明，使用 SZL P1-41 抑制 Skp2，不仅导致半胱天冬酶介导的细胞凋亡，而且增强了 BCP-ALL 细胞系（NALM-6 和 SUP-B15）中阿霉素诱导的细胞凋亡。SZL P1-41 联合阿霉素改变了 BCP-ALL 细胞的细胞周期分布以及细胞周期蛋白和细胞周期蛋白依赖性激酶的水平。在两种细胞系中，存在阿霉素和 SZL P1-41 时，DNA 损伤反应基因也被上调。总之，我们的结果表明，单独或联合使用阿霉素抑制 Skp2 可能在未来治疗 BCP-ALL 方面具有前景。
