Downregulation of POLD4 in Calu6 cells results in G1-S blockage through suppression of the Akt-Skp2-p27 pathway

Qinmiao Huang; Motoshi Suzuki; Yiming Zeng; Huaping Zhang; Dongyong Yang; Huihuang Lin

doi:10.1016/j.bmcl.2014.02.033

Downregulation of POLD4 in Calu6 cells results in G1-S blockage through suppression of the Akt-Skp2-p27 pathway

Bioorg Med Chem Lett. 2014 Apr 1;24(7):1780-3. doi: 10.1016/j.bmcl.2014.02.033. Epub 2014 Feb 20.

Authors

Qinmiao Huang¹, Motoshi Suzuki², Yiming Zeng³, Huaping Zhang³, Dongyong Yang³, Huihuang Lin³

Affiliations

¹ Department of Pulmonary Medicine, Second Affiliated Hospital of Fujian Medical University, Fujian, China. Electronic address: [email protected].
² Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Pulmonary Medicine, Second Affiliated Hospital of Fujian Medical University, Fujian, China.

PMID: 24618301
DOI: 10.1016/j.bmcl.2014.02.033

Abstract

Previously, we have shown that downregulation of POLD4 in lung cancer cells delays progression through the G1-S cell cycle transition and leads to increased genomic instability. To date however, detailed molecular mechanisms have not been elucidated to explain how this occurs. In the present study, we found that reduction in POLD4 by siRNA knockdown promoted downregulation of both p-Akt Ser473 and Skp2 as well as upregulation of p27. Furthermore, these protein expression levels were rescued when siRNA-resistant POLD4 was ectopically expressed in the knockdown cells. These data suggest that the POLD4 downregulation is associated with impaired Akt-Skp2-p27 pathway in lung cancer.

Keywords: Checkpoint; DNA repair; DNA replication; Lung cancer; POLD4; Skp2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p27 / antagonists & inhibitors*
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
DNA Polymerase III / antagonists & inhibitors*
DNA Polymerase III / metabolism
Dose-Response Relationship, Drug
Down-Regulation / drug effects
G1 Phase / drug effects
Humans
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
RNA, Small Interfering / pharmacology*
S Phase / drug effects
S-Phase Kinase-Associated Proteins / antagonists & inhibitors*
S-Phase Kinase-Associated Proteins / metabolism
Structure-Activity Relationship

Substances

RNA, Small Interfering
S-Phase Kinase-Associated Proteins
Cyclin-Dependent Kinase Inhibitor p27
Proto-Oncogene Proteins c-akt
POLD4 protein, human
DNA Polymerase III