Alhujaily, Muhanad Musaad M. (2019) Tumour metabolism of methylglyoxal as a target for treatment of glyoxalase1-linked multidrug resistance in cancer chemotherapy. PhD thesis, University of Warwick.

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Abstract

The glyoxalase system is the major pathway for metabolism of the reactive dicarbonyl metabolites, methylglyoxal (MG) in human cells. It is comprised of two enzymes, glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2). These enzymes catalyse the metabolism of MG into D-lactate via intermediate called S-D-lactoylglutathione. MG is produced in glycolysis as a by-product by the trace-level degradation of triosephosphate glycolytic intermediates. The main physiological function of Glo1 is cytoprotective, suppressing the steady-state concentration of MG to low tolerable levels. Cytotoxicity of MG is linked to its reaction with cell protein and DNA, leading to activation of apoptosis. Overexpression of Glo1 in tumour cells is a mediator of multidrug resistance in cancer chemotherapy and cell permeable inhibitors of Glo1 have anticancer activity, suggesting that cytotoxicity of MG may have a key role in cancer chemotherapy. The host research suggested that increased Glo1 expression is permissive of high glycolytic rate and growth of many tumours. My project emerged from this to study evidence of Glo1 expression as a negative survival factor in cancer therapy and the proteomic mechanism of cytotoxicity of MG to human tumour cells.

I accessed databases of gene expression in the public domain: KM Plotter – gene expression with links to breast cancer patient survival; and Cancer Cell Line Encyclopaedia (CCLE) – gene expression of human tumour cell lines. assessement between the association of Glo1 expression in cancer patients to effectiveness of treatment (progression free survival) and in human tumour cell lines to other gene expression were performed. Also investigated proteomic changes during MG-induced cytotoxicity in human HEK293 in vitro.

Key findings were: Glo1 is a negative survival factor in breast cancer – hazard ratio 1.37 (1.22 – 1.53), logrank P = 2.8 x 10-8 (n = 3951); applicable for all treatments, genotypes, intrinsic subtypes and stages of breast cancers. In human tumour cell lines, Glo1 expression correlated positively with GLO1 copy number and with genes enriched in spliceosome, RNA transport, and cell cycle and DNA replication pathways, and negatively with apoptosis adaptor TRADD. In proteomics analysis of MG-induced cytotoxicity, the mitochondrial apoptosis pathway was activated and proteins of the ribosome, spliceosome, RNA transport, proteasome, respiratory electron transport, ATP formation by chemiosmotic coupling and gluconeogenesis were decreased.

It is conclude that Glo1 impacts negatively on breast cancer survival and is a potential target for improved cancer therapy with Glo1 inhibitors where associated MG-induced cytotoxicity involves impairment of multiple processes, including spliceosome function.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology R Medicine > RA Public aspects of medicine R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Tumors, Metabolism , Glyoxalase, Glyoxal, Cancer, Chemotherapy
Official Date:	April 2019
Dates:	Date Event April 2019 Published
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Thornalley, Paul J.; Rabbani, Naila; Grammatopoulos, Dimitris
Sponsors:	University of Bisha
Format of File:	pdf
Extent:	223 leaves: illustrations, charts, plates
Language:	eng

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