Expression of the tumor suppressor ARHI inhibits the growth of pancreatic cancer cells by inducing G1 cell cycle arrest.
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 G1 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) p21WAF1, through the accumulation of p53 protein by the inhibition of PI-3K/AKT signaling. In addition, ARHI enhances expression of CKI p27kip1 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 G1 regulatory proteins, such as p21WAF1, p27kip1, CDK2, CDK4 and cyclins A and D1. ARHI represents a modulator of cancer cell proliferation and may play an important role in the development of pancreatic cancer.
Lu
Xinqing
X
Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, PR China.
Qian
Jiaming
J
Yu
Yinhua
Y
Yang
Hong
H
Li
Jingnan
J
D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C117386:DIRAS3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D020741:rho GTP-Binding Proteins