RRC ID 57874
Author Taniguchi K, Ii H, Kageyama S, Takagi H, Chano T, Kawauchi A, Nakata S.
Title Depletion of gamma-glutamylcyclotransferase inhibits cancer cell growth by activating the AMPK-FOXO3a-p21 axis.
Journal Biochem Biophys Res Commun
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.
Volume 517(2)
Pages 238-243
Published 2019-9-17
DOI 10.1016/j.bbrc.2019.07.049
PII S0006-291X(19)31399-3
PMID 31345573
MeSH AMP-Activated Protein Kinases / metabolism Cell Line, Tumor Cell Proliferation Down-Regulation Forkhead Box Protein O3 / metabolism Gene Expression Regulation, Neoplastic* Humans Neoplasms / genetics* Neoplasms / metabolism Neoplasms / pathology Phosphorylation Signal Transduction* gamma-Glutamylcyclotransferase / genetics* gamma-Glutamylcyclotransferase / metabolism p21-Activated Kinases / metabolism
IF 2.705
Times Cited 1
Human and Animal Cells PC-3(RCB2145) A172(RCB2530)