State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, College of Biotechnology, Southwest University , Chongqing , China.
Cell Cycle. 2019 Sep;18(18):2293-2306. doi: 10.1080/15384101.2019.1644913. Epub 2019 Jul 26.
Cytosine arabinoside (Ara-c) is a pyrimidine anti-metabolite that is capable of interfering with cellular proliferation by inhibiting DNA synthesis. Each inhibitor of cyclin-dependent kinase 4 (INK4) family member has the ability to bind to cyclin-dependent kinase 4 (CDK4) and inhibit the formation of the cell cycle-dependent CDK4/cyclin D1 complex, subsequently leading to cell cycle arrest in the G1/S phase. In this study, the expression of INK4 family genes in kidney cancer and the impact of these genes on patient prognosis were examined. Additionally, the effects of INK4 family genes and Ara-c on cell proliferation and tumor formation and development were examined. Finally, a potential association between Ara-c-induced cell cycle arrest and INK4-associated gene expression was evaluated. An upregulation of INK4 family genes was found to be positively correlated with the prognosis of patients with kidney cancer. Both the INK4 family genes and Ara-c were shown to induce cell cycle arrest and inhibit tumor formation and development. Moreover, Ara-c-induced cell cycle arrest was found to be associated with an Ara-c-induced upregulation of INK4 family gene expression, which ultimately inhibited the formation of the CDK4/cyclin D1 complex. These findings suggested that an upregulation of INK4 family genes has a positive effect on kidney cancer prognosis and can inhibit the formation and development of tumors. Moreover, Ara-c was shown to promote the upregulation of INK4 family genes, at the same time, Ara-c could directly regulate the cell cycle-dependent genes and (), independent of the INK4 family genes.
阿糖胞苷（Ara-c）是一种嘧啶类抗代谢物，能够通过抑制 DNA 合成来干扰细胞增殖。细胞周期蛋白依赖性激酶 4（CDK4）家族成员的每个抑制剂都能够与 CDK4 结合并抑制细胞周期依赖性 CDK4/细胞周期蛋白 D1 复合物的形成，随后导致细胞周期停滞在 G1/S 期。在这项研究中，检查了肾癌细胞中 INK4 家族基因的表达以及这些基因对患者预后的影响。此外，还检查了 INK4 家族基因和 Ara-c 对细胞增殖和肿瘤形成和发展的影响。最后，评估了 Ara-c 诱导的细胞周期停滞与 INK4 相关基因表达之间的潜在关联。INK4 家族基因的上调与肾细胞癌患者的预后呈正相关。INK4 家族基因和 Ara-c 均能诱导细胞周期停滞并抑制肿瘤形成和发展。此外，Ara-c 诱导的细胞周期停滞与 Ara-c 诱导的 INK4 家族基因表达上调有关，这最终抑制了 CDK4/细胞周期蛋白 D1 复合物的形成。这些发现表明 INK4 家族基因的上调对肾细胞癌的预后有积极影响，并能抑制肿瘤的形成和发展。此外，Ara-c 被证明能促进 INK4 家族基因的上调，同时，Ara-c 可以直接调节细胞周期依赖性基因和 （），而不依赖于 INK4 家族基因。
