Li Chunsheng, Qi Ling, Bellail Anita C, Hao Chunhai, Liu Tongjun
Department of Colorectal Surgery, The Third Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
Department of Pathology, Jilin Medical College, Jilin, Jilin 132013, P.R. China.
Oncol Lett. 2014 May;7(5):1673-1678. doi: 10.3892/ol.2014.1957. Epub 2014 Mar 10.
Preclinical and clinical studies have demonstrated the anticancer activity of PD-0332991, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, in the treatment of various types of cancer in a retinoblastoma protein (RB)-dependent manner. However, it remains unclear whether CDK4, CDK6 or both are required for RB phosphorylation in colorectal carcinoma and thus PD-0332991 can be used to target this CDK-RB axis for the cancer therapy. The aim of this study was to determine whether CDK4, CDK6 and phosphorylated RB proteins were overexpressed in colorectal carcinoma tissues as compared to matched normal colorectal tissues. The results showed that knockdown of CDK6 but not CDK4 reduced RB phosphorylation and inhibited carcinoma cell growth. Thus, CDK6 plays a critical role in RB phosphorylation and cancer growth. PD-0332991 treatment blocked RB phosphorylation and inhibited cell growth through the induction of G1 arrest of colorectal carcinoma cells. The results demonstrated that, by targeting of CDK6-RB axis, PD-0332991 may prove to be a novel therapeutic agent in treating colorectal carcinoma.
临床前和临床研究已证明，选择性细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂PD-0332991以视网膜母细胞瘤蛋白（RB）依赖性方式治疗多种类型癌症时具有抗癌活性。然而，在结直肠癌中，RB磷酸化是否需要CDK4、CDK6或两者都需要尚不清楚，因此PD-0332991是否可用于靶向该CDK-RB轴进行癌症治疗仍不明确。本研究的目的是确定与配对的正常结直肠组织相比，CDK4、CDK6和磷酸化RB蛋白在结直肠癌组织中是否过表达。结果显示，敲低CDK6而非CDK4可降低RB磷酸化并抑制癌细胞生长。因此，CDK6在RB磷酸化和癌症生长中起关键作用。PD-0332991处理可通过诱导结直肠癌细胞的G1期阻滞来阻断RB磷酸化并抑制细胞生长。结果表明，通过靶向CDK6-RB轴，PD-0332991可能被证明是治疗结直肠癌的一种新型治疗药物。
