Wang Q M, Feinman R, Kashanchi F, Houghton J M, Studzinski G P, Harrison L E
Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103, USA.
Clin Cancer Res. 2000 Jul;6(7):2951-8.
Differentiation agents use existing cellular systems to induce neoplastic cells to regain a normal phenotype and/or to cause growth arrest and therefore may offer novel chemotherapeutic approaches to treating solid tumors. In this study, we demonstrate in Caco-2 colon cancer cells that the differentiation agent phenylbutyrate (PB) causes a decrease in viable cells, an increase in cell differentiation, and a G1-S-phase block. The mechanism of this last effect is related to a PB-induced increase in p27Kip1, leading to a decrease in the activity of cyclin-dependent kinase 2 (CDK2), a positive regulator of the G1-S-phase cell cycle transition. Consistent with the decreased CDK2 kinase activity, we also observed a decrease in the phosphorylation state of the retinoblastoma protein after PB treatment. This was associated with increased binding and consequent inactivation of E2F, a transactivator of genes that regulate the G1 to S phase cell cycle transition. These data suggest that the differentiation agent PB inhibits tumor growth by limiting the availability of active E2F, with a subsequent G1-S-phase block. Additional studies should show whether PB is a clinically effective therapeutic agent against colorectal cancer.
分化诱导剂利用现有的细胞系统诱导肿瘤细胞恢复正常表型和/或导致生长停滞，因此可能为实体瘤的治疗提供新的化疗方法。在本研究中，我们在Caco-2结肠癌细胞中证明，分化诱导剂苯丁酸钠（PB）可导致活细胞数量减少、细胞分化增加以及G1-S期阻滞。最后这种效应的机制与PB诱导的p27Kip1增加有关，导致细胞周期蛋白依赖性激酶2（CDK2）活性降低，CDK2是G1-S期细胞周期转换的正向调节因子。与CDK2激酶活性降低一致，我们还观察到PB处理后视网膜母细胞瘤蛋白的磷酸化状态降低。这与E2F的结合增加以及随后的失活有关，E2F是调节G1到S期细胞周期转换的基因的反式激活因子。这些数据表明，分化诱导剂PB通过限制活性E2F的可用性来抑制肿瘤生长，随后导致G1-S期阻滞。进一步的研究应表明PB是否是一种针对结直肠癌的临床有效治疗药物。
