Abstract
Growth arrest and DNA damage-inducible (GADD) 45 and GADD153 proteins have been implicated in DNA repair, cell cycle regulation and growth arrest along with numerous other cellular mechanisms. In recent years, evidence has emerged that proteins encoded by these genes play pivotal roles in tumor suppression and apoptotic cell death. Thus, compounds altering the expression of these genes are likely to be of interest in cancer prevention and/or treatment. Protocatechualdehyde is isolated from Phellinus gilvus and has been investigated as a promising cancer preventive agent because of its medicinal properties. This mushroom belongs to Hymenochaetaceae Basidiomycetes, and has advantages over many Phellinus species due to short growth period (3 months), making production cost-effective. The exact molecular mechanisms of protocatechualdehyde are not clearly understood. Based on studies of pro-apoptotic activity of protocatechualdehyde in T-cells and colorectal cancer cells, we examined the relationship between the expression of GADD45 and GADD153 and apoptosis induction in human lung cancer cell line PC-9. We report a p53-independent increase in GADD45 and GADD153 expression by protocatechualdehyde. Likewise, the proliferation of PC-9 cells is inhibited via a G1/S arrest of the cell-cycle stimulating apoptosis. Further, induction of apoptosis was inhibited in PC-9 cells knocked down for GADD45 and GADD153. Protocatechualdehyde treatment also induced the expression of cell cycle inhibitors p21 and p27, while inhibiting Bcl-2, cyclin D1, CDK2, CDK4 and CDK6 genes. These findings suggest that upregulation of GADD45 and GADD153 proteins are the mechanism for protocatechualdehydei?½s anti-tumor activities.
Highlights
Growth arrest and DNA damage-inducible (GADD) 45 and GADD153 proteins have been implicated in DNA repair, cell cycle regulation and growth arrest along with numerous other cellular mechanisms
The G1/S checkpoint is primarily controlled by collective kinase activities of the complex of cyclin D with CDK4, CDK6 and cyclin E and these G1 kinases can in turn be regulated by cell cycle inhibitors, which may cause the cells to arrest at the G1 phase [29]
To evaluate the cell cycle inhibitor effect of protocatechualdehyde, we investigated changes in regulation of putative G1 cyclin such as cyclin D1 and the cyclin dependent kinase CDK2, CDK4, CDK6 and observed that cell-cycle arrest is associated with downregulation of these cell cycle regulators [30]
Summary
Growth arrest and DNA damage-inducible (GADD) 45 and GADD153 proteins have been implicated in DNA repair, cell cycle regulation and growth arrest along with numerous other cellular mechanisms. Evidence has emerged that proteins encoded by these genes play pivotal roles in tumor suppression and apoptotic cell death. The GADD45 expression is rapidly regulated at both transcriptional and post-transcriptional levels in response to genotoxic stress via p53 tumor suppressor pathway or by mRNA stability as well as other growth-arrest signals [1]. Because of the involvement of GADD45 protein with the cell cycle, apoptosis, DNA repair and stability makes it an obvious target for cancer therapy [2]. Previous studies show that GADD45 and GADD153 proteins play key roles in the induction of programmed cell death and we sought to investigate their role in human lung cancer. In this study two GADD genes (GADD45 and GADD153) were studied representing a p53dependent and a p53-independent pathway respectively
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