Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome

Muhanad Alhujaily; Hafsa Abbas; Mingzhan Xue; Alberto de la Fuente; Naila Rabbani; Paul J Thornalley

doi:10.3389/fonc.2021.748698

Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome

Front Oncol. 2021 Nov 1:11:748698. doi: 10.3389/fonc.2021.748698. eCollection 2021.

Authors

Muhanad Alhujaily^{1

2}, Hafsa Abbas², Mingzhan Xue^{2

3}, Alberto de la Fuente³, Naila Rabbani^{4

5}, Paul J Thornalley^{2

3}

Affiliations

¹ College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia.
² Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, United Kingdom.
³ Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
⁴ Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, Doha, Qatar.
⁵ Biomedical & Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar.

Abstract

Background: Tumor glycolysis is a target for cancer chemotherapy. Methylglyoxal (MG) is a reactive metabolite formed mainly as a by-product in anaerobic glycolysis, metabolized by glyoxalase 1 (Glo1) of the glyoxalase system. We investigated the role of MG and Glo1 in cancer chemotherapy related in multidrug resistance (MDR).

Methods: Human Glo1 was overexpressed in HEK293 cells and the effect on anticancer drug potency, drug-induced increase in MG and mechanism of cytotoxicity characterized. Drug-induced increased MG and the mechanisms driving it were investigated and the proteomic response to MG-induced cytotoxicity explored by high mass resolution proteomics of cytoplasmic and other subcellular protein extracts. Glo1 expression data of 1,040 human tumor cell lines and 7,489 tumors were examined for functional correlates and impact of cancer patient survival.

Results: Overexpression of Glo1 decreased cytotoxicity of antitumor drugs, impairing antiproliferative activity of alkylating agents, topoisomerase inhibitors, antitubulins, and antimetabolites. Antitumor drugs increased MG to cytotoxic levels which contributed to the cytotoxic, antiproliferative mechanism of action, consistent with Glo1-mediated MDR. This was linked to off-target effects of drugs on glycolysis and was potentiated in hypoxia. MG activated the intrinsic pathway of apoptosis, with decrease of mitochondrial and spliceosomal proteins. Spliceosomal proteins were targets of MG modification. Spliceosomal gene expression correlated positively with Glo1 in human tumor cell lines and tumors. In clinical chemotherapy of breast cancer, increased expression of Glo1 was associated with decreased patient survival, with hazard ratio (HR) = 1.82 (logrank p < 0.001, n = 683) where upper quartile survival of patients was decreased by 64% with high Glo1 expression.

Conclusions: We conclude that MG-mediated cytotoxicity contributes to the cancer chemotherapeutic response and targets the spliceosome. High expression of Glo1 contributes to multidrug resistance by shielding the spliceosome from MG modification and decreasing survival in the chemotherapy of breast cancer. Adjunct chemotherapy with Glo1 inhibitor may improve treatment outcomes.

Keywords: cancer chemotherapy; glyoxalase; methylglyoxal; multidrug resistance; proteomics.