Identification of c-Met as a novel target of & gamma;-glutamylcyclotransferase

& gamma;-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.

Automated summary

GGCT is highly expressed in cancer cells and its knockdown inhibits cancer cell growth. The knockdown of GGCT inhibits the MEK-ERK pathway and activates the tumor suppressor gene RB at the protein level. GGCT knockdown also decreases c-Met expression and reverses the inhibition of the STAT3-c-Met-MEK-ERK pathway through AMPK activation. These findings suggest that GGCT knockdown activates the RB protein by inhibiting the STAT3-c-Met-MEK-ERK pathway via AMPK activation.