期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 517, 期 2, 页码 238-243出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2019.07.049
关键词
Gamma-glutamylcyclotransferase; AMP-Activated protein kinase; Forkhead box O transcription factor 3a; p21(WAF1/CIP1); Cancer cell growth inhibition
资金
- Japan Society for the Promotion of Science [15K10584, 16K08722, 26461436]
- Ministry of Education, Culture, Sports, Science and Technology-Supported Programfor the Strategic Research Foundation at Private Universities [2015e2019]
- Takeda Science Foundation
- Kyoto Pharmaceutical University Fund for the Promotion of Scientific Research
- Grants-in-Aid for Scientific Research [15K10584, 16K08722] Funding Source: KAKEN
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 p21(WAF1/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) alpha, 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. (C) 2019 Elsevier Inc. All rights reserved.
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