Depletion of gamma-glutamylcyclotransferase inhibits cancer cell growth by activating the AMPK-FOXO3a-p21 axis.

Abstract

Inhibition of gamma-glutamylcyclotransferase (GGCT), which is highly expressed in various cancer tissues, exerts anticancer effects both in vitro and in vivo. Previous studies have shown that depletion of GGCT blocks the growth of MCF7 breast cancer cells via upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21); in addition, induction of autophagy plays a role in the upregulation of p21 upon GGCT knockdown. However, the mechanisms underlying induction of p21 in cancer cells are not fully understood. Here, we show that GGCT knockdown in PC3 human prostate cancer and A172 glioblastoma cells upregulates the mRNA and nuclear protein levels of Forkhead box O transcription factor 3a (FOXO3a), a transcriptional factor involved in tumor suppression. Simultaneous knockdown of FOXO3a and GGCT in PC3 and A172 cells attenuated upregulation of p21, followed by growth inhibition and cell death. Furthermore, simultaneous knockdown of GGCT and AMP-activated protein kinase (AMPK) α, a metabolic stress sensor, in PC3 and A172 cells led to marked attenuation of cellular responses induced by GGCT knockdown, including an increase in FOXO3a phosphorylation at Ser413, upregulation of p21, growth inhibition, and cell death. These results indicate that the AMPK-FOXO3a-p21 axis plays an important role in inhibition of cancer cell growth by depletion of GGCT.

• Authors: Keiko Taniguchi, Hiromi Ii, Susumu Kageyama, Hiroko Takagi, Tokuhiro Chano, Akihiro Kawauchi, Susumu Nakata
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 517 Issue 2 Pg. 238-243 (09 17 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 31345573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• p21-Activated Kinases
• AMP-Activated Protein Kinases
• gamma-Glutamylcyclotransferase

Topics

• AMP-Activated Protein Kinases (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation
• Forkhead Box Protein O3 (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms (genetics, metabolism, pathology)
• Phosphorylation
• Signal Transduction
• gamma-Glutamylcyclotransferase (genetics, metabolism)
• p21-Activated Kinases (metabolism)