Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome
<h3>Background</h3><p dir="ltr">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 o...
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| مؤلفون آخرون: | , , , , |
| منشور في: |
2021
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| _version_ | 1864513516132630528 |
|---|---|
| author | Muhanad Alhujaily (11630107) |
| author2 | Hafsa Abbas (9501821) Mingzhan Xue (3607649) Alberto de la Fuente (360936) Naila Rabbani (291722) Paul J. Thornalley (291723) |
| author2_role | author author author author author |
| author_facet | Muhanad Alhujaily (11630107) Hafsa Abbas (9501821) Mingzhan Xue (3607649) Alberto de la Fuente (360936) Naila Rabbani (291722) Paul J. Thornalley (291723) |
| author_role | author |
| dc.creator.none.fl_str_mv | Muhanad Alhujaily (11630107) Hafsa Abbas (9501821) Mingzhan Xue (3607649) Alberto de la Fuente (360936) Naila Rabbani (291722) Paul J. Thornalley (291723) |
| dc.date.none.fl_str_mv | 2021-11-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3389/fonc.2021.748698 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Studies_of_Glyoxalase_1-Linked_Multidrug_Resistance_Reveal_Glycolysis-Derived_Reactive_Metabolite_Methylglyoxal_Is_a_Common_Contributor_in_Cancer_Chemotherapy_Targeting_the_Spliceosome/25780986 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis methylglyoxal glyoxalase cancer chemotherapy multidrug resistance proteomics |
| dc.title.none.fl_str_mv | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">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).</p><h3>Methods</h3><p dir="ltr">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.</p><h3>Results</h3><p dir="ltr">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.</p><h3>Conclusions</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Frontiers in Oncology<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3389/fonc.2021.748698" target="_blank">https://dx.doi.org/10.3389/fonc.2021.748698</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_372264ffb6891f1a7f711a31c645dd88 |
| identifier_str_mv | 10.3389/fonc.2021.748698 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25780986 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the SpliceosomeMuhanad Alhujaily (11630107)Hafsa Abbas (9501821)Mingzhan Xue (3607649)Alberto de la Fuente (360936)Naila Rabbani (291722)Paul J. Thornalley (291723)Biomedical and clinical sciencesOncology and carcinogenesismethylglyoxalglyoxalasecancer chemotherapymultidrug resistanceproteomics<h3>Background</h3><p dir="ltr">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).</p><h3>Methods</h3><p dir="ltr">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.</p><h3>Results</h3><p dir="ltr">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.</p><h3>Conclusions</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Frontiers in Oncology<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3389/fonc.2021.748698" target="_blank">https://dx.doi.org/10.3389/fonc.2021.748698</a></p>2021-11-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3389/fonc.2021.748698https://figshare.com/articles/journal_contribution/Studies_of_Glyoxalase_1-Linked_Multidrug_Resistance_Reveal_Glycolysis-Derived_Reactive_Metabolite_Methylglyoxal_Is_a_Common_Contributor_in_Cancer_Chemotherapy_Targeting_the_Spliceosome/25780986CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/257809862021-11-01T00:00:00Z |
| spellingShingle | 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 (11630107) Biomedical and clinical sciences Oncology and carcinogenesis methylglyoxal glyoxalase cancer chemotherapy multidrug resistance proteomics |
| status_str | publishedVersion |
| title | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome |
| title_full | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome |
| title_fullStr | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome |
| title_full_unstemmed | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome |
| title_short | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome |
| title_sort | Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis methylglyoxal glyoxalase cancer chemotherapy multidrug resistance proteomics |