Expression of the tumor suppressor ARHI inhibits the growth of pancreatic cancer cells by inducing G1 cell cycle arrest
Expression of the tumor suppressor ARHI inhibits the growth of pancreatic cancer cells by inducing G1 cell cycle arrest
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肿瘤抑制因子 ARHI 的表达通过诱导 G1 细胞周期停滞来抑制胰腺癌细胞的生长
DOI：
10.3892/or_00000483
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发表时间：
2009-09-01
期刊：
影响因子：
4.2
通讯作者：
Li, Jingnan
中科院分区：
文献类型：
--
作者：
Lu, Xinqing;Qian, Jiaming;Li, Jingnan
Ras同源物成员I（ARHI）是一种印记肿瘤抑制基因，其表达在胰腺癌中经常丢失。这种小的GTP结合蛋白是Ras超家族的成员，与Ras具有显著的同源性。与Ras癌基因相反，ARHI已被证明具有抗增殖作用，但其抑制胰腺癌细胞增殖和诱导细胞周期停滞的机制仍不清楚。通过产生稳定的转染子，ARHI在已经失去表达的胰腺癌细胞中重新表达。流式细胞仪分析表明，ARHI阻断胰腺癌细胞的细胞周期进程在G1期。在ARHI转染子中，磷酸化AKT蛋白表达与载体转染子相比降低。ARHI的再表达通过抑制PI-3 K/AKT信号传导而增加p53蛋白的积累，从而增加细胞周期蛋白依赖性激酶（CDK）抑制剂（CKI）p21（WAF 1）的表达。此外，ARHI通过抑制PI-3 K/AKT信号传导增强CKI p27（kip 1）的表达。细胞周期蛋白A和D1的表达下降，而细胞周期蛋白E在相同的条件下不受影响。细胞周期蛋白依赖性激酶2（CDK 2）和4（CDK 4）的活性降低ARHI转染。这些结果表明，PI-3 K/AKT通路在胰腺癌的发病机制中起着关键作用，ARHI通过调节几个关键的G1调节蛋白如p21（WAF 1）、p27（kip 1）、CDK 2、CDK 4和cyclins A和131发挥其生长抑制作用。ARHI代表癌细胞增殖的调节剂，并可能在胰腺癌的发展中发挥重要作用。
A Ras homologue member I (ARHI) is an imprinted tumor suppressor gene whose expression is frequently lost in pancreatic cancers. This small GTP-binding protein is a member of the Ras superfamily with significant homology to Ras. In contrast to the Ras oncogene, ARHI has been shown to have anti-proliferative effects, but the mechanisms by which it inhibits pancreatic cancer cell proliferation and induces cell cycle arrest remain unclear. By generating stable transfectants, ARHI was reexpressed in pancreatic cancer cells that had lost its expression. Flow cytometry analysis indicated that ARHI blocked cell cycle progression at the G, phase in pancreatic cancer cells. In ARHI transfectants, phosphorylated AKT protein expression decreased compared to that of vector transfectants. Reexpression of ARHI increased the expression of the cyclin-dependent kinase (CDK) inhibitor (CKI) p21(WAF1), through the accumulation of p53 protein by the inhibition of PI-3K/AKT signaling. In addition, ARHI enhances expression of CKI p27(kip1) through the inhibition of PI-3K/AKT signaling. The expression of cyclins A and D1 decreased, while cyclin E was not affected under the same conditions. The activities of cyclin-dependent kinases 2 (CDK2) and 4 (CDK4) were reduced in ARHI transfectants. These results suggest that the PI-3K/AKT pathway plays a pivotal role in the pathogenesis of pancreatic cancer and ARHI exerts its growth-inhibitory effects through modulation of several key G, regulatory proteins, such as p21(WAF1), p27(kip1), CDK2, CDK4 and cyclins A and 131. ARHI represents a modulator of cancer cell proliferation and may play an important role in the development of pancreatic cancer.