Abstract
GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and the mechanisms underlying this activity remain largely unknown. Our purpose was to investigate the antitumor effects of depleted GLOI on CRC in vitro and in vivo. RNA interference was used to deplete GLOI activity in four CRC cell lines. The cells’ proliferation, apoptosis, migration, and invasion were assessed by using the Cell Counting Kit-8, plate colony formation assay, flow cytometry, and transwell assays. Protein and mRNA levels were analyzed by western blot and quantitative real-time PCR (qRT-PCR), respectively. The antitumor effect of GLOI depletion in vivo was investigated in a SW620 xenograft tumor model in BALB/c nude mice. Our results show that GLOI is over-expressed in the CRC cell lines. GLOI depletion inhibited the proliferation, colony formation, migration, and invasion and induced apoptosis of all CRC cells compared with the controls. The levels of signal transducer and activator of transcription 1 (STAT1), p53, and Bcl-2 assaciated X protein (Bax) were upregulated by GLOI depletion, while cellular homologue of avian myelocytomatosis virus oncogene (c-Myc) and B cell lymphoma/lewkmia-2 (Bcl-2) were downregulated. Moreover, the growth of SW620-induced CRC tumors in BALB/c nude mice was significantly attenuated by GLOI depletion. The expression levels of STAT1, p53, and Bax were increased and those of c-Myc and Bcl-2 were decreased in the GLOI-depleted tumors. Our findings demonstrate that GLOI depletion has an antitumor effect through the STAT1 or p53 signaling pathways in CRC, suggesting that GLOI is a potential therapeutic target.
Highlights
Colorectal cancer (CRC) is the third most common cancer in the U.S and the third leading cause of cancer mortality among both men and women [1]
Our findings show that GLOI was overexpressed in the CRC cell lines tested
Our study demonstrated that GLOI was over-expressed in the CRC cells
Summary
Colorectal cancer (CRC) is the third most common cancer in the U.S and the third leading cause of cancer mortality among both men and women [1]. 2 of 17 2 of 17 sisursguerrgyerwy iwthithadajdujnucnticvtievechcehmemotohtehrearpaypyanadnd/o/rorardaidoitohtehrearpayp,y,bbuut ttatargrgeeteteddtthheerraappyy aanndd immune therapy are being introduced into the clinical setting [2,3]. These emerging comprehensive approaches have imprrovveedd tthheerraappeeuuttiicceeffffiiccaaccyy, the rates of recurrence and metastaassiiss rremmaaiinn hhiigghh,, resulting in an overall low survival rate and poor prognosis [2,3,4,5,6]. YTlhgelyseoxfianldfionrgms asutigognesletdthtaot GacLcOumI pullaaytisoancoruf cmiaeltrhoylelgilnyotuxmaloarnigdencyestoist.oxicity [22,23]. These findings suggest that GLOI plays a cruAcilatlhroouleghinGtuLmOoI rhigaesnbeesiesn. LOI on CRC cells in vitro and in vivo and the molecular mechanisms underlying these effects
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