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Updated: Jul 22, 2025
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
Identification of c-Met as a novel target of γ-glutamylcyclotransferase
Yumiko Saito1,2, Keiko Taniguchi3, Hiromi Ii4
1Department of Drug Discovery Medicine, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kawaramachi-Hirokoji Kamigyo-ku, Kyoto, 602-8566, Japan.
Abstract:
γ-Glutamylcyclotransferase (GGCT) is highly expressed in multiple types of cancer tissues and its knockdown suppresses the growth of cancer cells in vitro and in vivo. Although GGCT is a promising target for cancer therapy, the mechanisms underlying the antitumor effects remain unclear. The knockdown of GGCT inhibited the MEK-ERK pathway, and activated the tumor suppressor retinoblastoma gene (RB) at the protein level in cancer cell lines. c-Met was down-regulated by the knockdown of GGCT in cancer cells and its overexpression attenuated the dephosphorylation of RB and cell cycle arrest induced by the knockdown of GGCT in lung cancer A549 cells. STAT3 is a transcription factor that induces c-Met expression. STAT3 phosphorylation and its nuclear expression level were decreased in GGCT-depleted A549 and prostate cancer PC3 cells. The simultaneous knockdown of AMPK and GGCT restored the down-regulated expression of c-Met, and attenuated the dephosphorylation of STAT3 and MEK-ERK-RB induced by the knockdown of GGCT in PC3 cells. An intraperitoneal injection of a GGCT inhibitor decreased c-Met protein expression in a mouse xenograft model of PC3 cells. These results suggest that the knockdown of GGCT activates the RB protein by inhibiting the STAT3-c-Met-MEK-ERK pathway via AMPK activation.
Insights
γ-Glutamylcyclotransferase (GGCT) knockdown inhibits cancer growth by activating the tumor suppressor RB protein. This occurs through the inhibition of the STAT3-c-Met-MEK-ERK pathway, suggesting GGCT as a potential cancer therapy target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- γ-Glutamylcyclotransferase (GGCT) is highly expressed in various cancers and its inhibition suppresses tumor growth.
- The precise molecular mechanisms behind GGCT's antitumor effects are not fully understood.
- GGCT is a potential therapeutic target for cancer treatment.
Purpose of the Study:
- To elucidate the underlying molecular mechanisms of GGCT's antitumor effects.
- To investigate the role of GGCT in regulating key signaling pathways involved in cancer progression.
- To identify potential therapeutic strategies targeting GGCT.
Main Methods:
- Knockdown of GGCT in cancer cell lines (A549, PC3) and a mouse xenograft model.
- Analysis of signaling pathway components including MEK-ERK, retinoblastoma gene (RB), STAT3, c-Met, and AMPK.
- Assessment of protein levels, phosphorylation status, and nuclear expression.
Main Results:
- GGCT knockdown inhibited the MEK-ERK pathway and activated RB protein.
- GGCT depletion led to decreased c-Met and STAT3 phosphorylation/nuclear expression.
- Simultaneous knockdown of AMPK and GGCT modulated these pathways, suggesting AMPK's involvement.
- GGCT inhibition decreased c-Met expression in a mouse xenograft model.
Conclusions:
- GGCT knockdown activates the tumor suppressor RB protein.
- This activation is mediated by the inhibition of the STAT3-c-Met-MEK-ERK signaling cascade.
- AMP-activated protein kinase (AMPK) activation plays a role in the observed effects.
- Targeting GGCT may represent a viable strategy for cancer therapy.
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