A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells

Antognelli, Cinzia; Mezzasoma, Letizia; Fettucciari, Katia; Talesa, Vincenzo Nicola

doi:10.1016/j.biocel.2013.01.003

Cited by 62 publications

(64 citation statements)

References 61 publications

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“…[12][13][14][25][26][27][28] The anti-tumor role of MG may also be attributed to its effects on cell migration. 15 Our results showing that MG inhibited the viability, proliferation, migration, and invasion of DLD-1 and SW480 colon cancer cells while promoting their apoptosis are in accordance with previous results in other cancer types.…”

Section: Discussionmentioning

confidence: 99%

“…15 Our results showing that MG inhibited the viability, proliferation, migration, and invasion of DLD-1 and SW480 colon cancer cells while promoting their apoptosis are in accordance with previous results in other cancer types. [12][13][14][25][26][27][28] There are multiple potential mechanisms by which MG may induce tumor suppression: (1) inhibition of the synthesis of proteins and nucleic acids via irreversible modification of protein, DNA, and RNA;…”

Section: Discussionmentioning

confidence: 99%

“…11 MG induces apoptosis through multiple mechanisms such as accumulating reactive oxygen species and advanced glycation end products and triggering the mitochondrial apoptotic pathway. [12][13][14] MG also inhibits tumor metastasis, enhances the immune response, and increases sensitivity to anti-tumor agents. [15][16][17][18] c-Myc is one of the most widely expressed human protooncogenes and is frequently overexpressed in colon cancer.…”

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression

Zhou

et al. 2016

Cancer Biology & Therapy

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Methylglyoxal (MG) is a highly reactive dicarbonyl compound exhibiting anti-tumor activity. The antitumor effects of MG have been demonstrated in some types of cancer, but its role in colon cancer and the mechanisms underlying this activity remain largely unknown. We investigated its role in human colon cancer and the underlying mechanism using human colon cancer cells and animal model. Viability, proliferation, and apoptosis were quantified in DLD-1 and SW480 colon cancer cells by using the Cell Counting Kit-8, plate colony formation assay, and flow cytometry, respectively. Cell migration and invasion were assessed by wound healing and transwell assays. Glucose consumption, lactate production, and intracellular ATP production also were assayed. The levels of c-Myc protein and mRNA were quantitated by western blot and qRT-PCR. The anti-tumor role of MG in vivo was investigated in a DLD-1 xenograft tumor model in nude mice. We demonstrated that MG inhibited viability, proliferation, migration, and invasion and induced apoptosis of DLD-1 and SW480 colon cancer cells. Treatment with MG reduced glucose consumption, lactate production, and ATP production and decreased c-Myc protein levels in these cells. Moreover, MG significantly suppressed tumor growth and c-Myc expression in vivo. Our findings suggest that MG plays an anti-tumor role in colon cancer. It inhibits cancer cell growth by altering the glycolytic pathway associated with downregulation of c-Myc protein. MG has therapeutic potential in colon cancer by interrupting cancer metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression

Zhou

et al. 2016

Cancer Biology & Therapy

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“…In addition, if methylglyoxal is not efficiently catalyzed by GLO1, the increased levels of methylglyoxal and AGEs induce the activation of p38/MAPK signaling, and reduce the activation of NF-κB signaling. This leads to the enhanced expression of the pro-apoptotic Bax and P53, and the decreased expression of the anti-apoptotic proteins, such as X-linked inhibitor of apoptosis protein (XIAP), survivin, Bcl-2 and Bcl-xL [31,32]. Therefore, GLO1 amplification and the increased expression and activity of GLO1 facilitate the detoxification of intracellular glyoxal and methylglyoxal to ensure tumor cell survival and proliferation.…”

Section: Regulatory Mechanisms Of Gloi In Tumor Cell Proliferation Anmentioning

confidence: 99%

Glyoxalase I in Tumor Cell Proliferation and Survival and as a Potential Target for Anticancer Therapy

Geng

Ma²,

Zhang³

et al. 2014

Oncol Res Treat

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SummaryGlyoxalase I (GLO1) belongs to the glyoxalase system, which catalyzes the conversion of deleterious methylglyoxal, mainly produced by glycolysis, to non-toxic D-lactate. The expression of GLO1 was up-regulated in tumor tissues with high metabolic rate, whereas inhibition of GLO1 expression led to the accumulation of glyoxal and methylglyoxal, significantly inducing cell damage or apoptosis. This suggests that GLO1 may play an important role in tumor cell proliferation and survival, and may represent a potential therapeutic target for tumors. Moreover, overexpression of GLO1 was associated with multidrug resistance in cancer chemotherapy. This review describes the role of GLO1 in tumor cell proliferation and survival, and the potential of GLO1 as a biomarker for tumor diagnosis and as a target for anticancer drug development.

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“…Overexpression of Glo1 in PCa cells would aim at maintaining low intracellular levels of the glycolysis-derived cytotoxic metabolite MG, as a survival defense strategy. Indeed, in vitro studies performed with PCa cell lines, causatively demonstrated this role [24,25,36], in addition to pointing out a pro-survival function for this protein by eluding apoptosis in a mechanism involving the desensitization of NF-kB pathway [25]. Only one study, based on the proteomic analysis of normal and malignant prostate tissues, identified Glo1 among the proteins lost in PCa [56].…”

Section: Glo1mentioning

confidence: 99%

Glyoxalases in Urological Malignancies

Antognelli¹,

Talesa²

2017

Preprint

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Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide and although advances have been made toward understanding the molecular basis of these diseases, a complete insight of the pathogenic mechanisms is still a research challenge for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these neoplasms for which no effective therapies exist. Glyoxalases are enzymes that catalyzes the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggest that glyoxalases, especially Glo1, would act as oncogenes in urological malignancies and be central to their initiation, growth and progression. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-PCa therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis.

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A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells

Cited by 62 publications

References 61 publications

Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression

Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression

Glyoxalase I in Tumor Cell Proliferation and Survival and as a Potential Target for Anticancer Therapy

Glyoxalases in Urological Malignancies

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