GLO1 overexpression in human malignant melanoma

Abstract

Glyoxalase I [lactoylglutathione lyase (EC 4.4.1.5) encoded by GLO1] is a ubiquitous cellular defense enzyme involved in the detoxification of methylglyoxal, a cytotoxic byproduct of glycolysis. Accumulative evidence suggests an important role of GLO1 expression in protection against methylglyoxal-dependent protein adduction and cellular damage associated with diabetes, cancer, and chronological aging. Based on the hypothesis that GLO1 upregulation may play a functional role in glycolytic adaptations of cancer cells, we examined GLO1 expression status in human melanoma tissue. Quantitative RT-PCR analysis of a cDNA tissue array containing 40 human melanoma tissues (stages III and IV) and 13 healthy controls revealed pronounced upregulation of GLO1 expression at the mRNA level. Immunohistochemical analysis of a melanoma tissue microarray confirmed upregulation of glyoxalase 1 protein levels in malignant melanoma tissue versus healthy human skin. Consistent with an essential role of GLO1 in melanoma cell defense against methylglyoxal cytotoxicity, siRNA interference targeting GLO1-expression (siGLO1) sensitized A375 and G361 human metastatic melanoma cells towards the antiproliferative, apoptogenic, and oxidative stress-inducing activity of exogenous methylglyoxal. Protein adduction by methylglyoxal was increased in siGLO1-transfected cells as revealed by immunodetection using a monoclonal antibody directed against the major methylglyoxal-derived epitope argpyrimidine that detected a single band of methylglyoxal-adducted protein in human LOX, G361, and A375 total cell lysates. Using 2D-proteomics followed by mass spectrometry the methylglyoxal-adducted protein was identified as heat shock protein 27 (Hsp27; HSPB1). Taken together, our data suggest a function of GLO1 in the regulation of detoxification and target-adduction by the glycolytic byproduct methylglyoxal in malignant melanoma.

Glyoxalase-I Is a Novel Prognosis Factor Associated with Gastric Cancer Progression

“…GLO1 expression is increased in several human cancers of the colon, breast, prostate, and melanoma [13], [14], [15], [16], [17]. Recent studies have reported that over-expression of GLO1 is associated with cancer progression and drug resistance [17].…”

Energy metabolism, proteotoxic stress and age-related dysfunction – Protection by carnosine

“…The strong association between MG and tumours in literature searches probably reflects the fact that increased MG levels in tumour cells can induce cell death Blair et al, 2010). Tumour cells are primarily glycolytic in their energy generation, as outlined by the so-called Warburg effect (Herling et al, 2011;Israel and Schwartz, 2011).…”

Blockage of Glyoxalase I Inhibits Colorectal Tumorigenesis and Tumor Growth via Upregulation of STAT1, p53, and Bax and Downregulation of c-Myc and Bcl-2

“…Overexpression of GLOI has been documented in numerous tumor tissues and cells, including colon, breast, prostate, lung, stomach, endometrial, and ovarian cancers [11,12,13,14,15,16,17,18,19]. GLOI overexpression has been associated with cancer cell survival and resistance to chemotherapeutic agents [20,21].…”