PD-0332991 induces G1 arrest of colorectal carcinoma cells through inhibition of the cyclin-dependent kinase-6 and retinoblastoma protein axis.
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.
Department of Colorectal Surgery, The Third Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
Chunsheng
C
Li
Department of Pathology, Jilin Medical College, Jilin, Jilin 132013, P.R. China.
Ling
L
Qi
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada.
Anita C
AC
Bellail
Department of Pathology, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada.
Chunhai
C
Hao
Department of Colorectal Surgery, The Third Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
Tongjun
T
Liu
PD-0332991; cell cycle; colorectal carcinoma; cyclin-dependent kinase-6; retinoblastoma protein