Molecule Information

General Information of the Molecule (ID: Mol00498)

• Name: Methylated-DNA--protein-cysteine methyltransferase (MGMT) ,Homo sapiens
• Synonyms: 6-O-methylguanine-DNA methyltransferase; MGMT; O-6-methylguanine-DNA-alkyltransferase
• Molecule Type: Protein
• Gene Name: MGMT
• Gene ID: 4255
• Location: chr10:129467190-129770983[+]
• Sequence:
  MDKDCEMKRTTLDSPLGKLELSGCEQGLHEIKLLGKGTSAADAVEVPAPAAVLGGPEPLM
  QCTAWLNAYFHQPEAIEEFPVPALHHPVFQQESFTRQVLWKLLKVVKFGEVISYQQLAAL
  AGNPKAARAVGGAMRGNPVPILIPCHRVVCSSGAVGNYSGGLAVKEWLLAHEGHRLGKPG
  LGGSSGLAGAWLKGAGATSGSPPAGRN
• Function: Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA. Repairs the methylated nucleobase in DNA by stoichiometrically transferring the methyl group to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.
• Uniprot ID: MGMT_HUMAN
• Ensembl ID: ENSG00000170430
• HGNC ID: HGNC:7059

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 7 drug(s) in total

Carmustine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Malignant glioma [1]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Carmustine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Disease Class: Anaplastic astrocytoma [1]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Resistant Drug: Carmustine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: For drugs that have evaded cytosolic mechanisms of drug resistance, the nucleus is equipped with the capacity to remove BCNU or temozolomide alkyl groups from the O6-position of guanine via a reaction catalyzed by MGMT. Repair occurs before cross-link formation and involves an irreversible stoichiometric covalent transfer of the O6-alkyl DNA adduct to a cysteine within the active site of MGMT, resulting in the inactivation and subsequent depletion of enzyme activity. MGMT-mediated repair is rapid, with a half-life of 35 hours. MGMT enzyme recovery occurs via de novo synthesis. In malignant glioma patients, MGMT overexpression has been associated with resistance to BCNU and similar alkylating agents and was an independent predictor of poor survival. MGMT is also thought to contribute to temozolomide resistance, which we did not detect in our study. This may be related to the in vitro pharmacokinetic differences between BCNU and temozolomide.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Malignant glioma [1]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Dacarbazine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Malignant glioma [1]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Dacarbazine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Malignant glioma [1]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Irinotecan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Malignant glioma [1]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Irinotecan
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Malignant glioma [2]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Temozolomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST was inversely correlated with miR29c, positively correlated with PS1, positively related with MGMT. XIST can inhibit miR29c expression by directly binding to miR29c and subsequently up-regulate the expression of SP1 and MGMT to promote the chemoresistance of glioma cells to TMZ.

Disease Class: Anaplastic astrocytoma [1]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Resistant Drug: Temozolomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: For drugs that have evaded cytosolic mechanisms of drug resistance, the nucleus is equipped with the capacity to remove BCNU or temozolomide alkyl groups from the O6-position of guanine via a reaction catalyzed by MGMT. Repair occurs before cross-link formation and involves an irreversible stoichiometric covalent transfer of the O6-alkyl DNA adduct to a cysteine within the active site of MGMT, resulting in the inactivation and subsequent depletion of enzyme activity. MGMT-mediated repair is rapid, with a half-life of 35 hours. MGMT enzyme recovery occurs via de novo synthesis. In malignant glioma patients, MGMT overexpression has been associated with resistance to BCNU and similar alkylating agents and was an independent predictor of poor survival. MGMT is also thought to contribute to temozolomide resistance, which we did not detect in our study. This may be related to the in vitro pharmacokinetic differences between BCNU and temozolomide.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma [3], [4]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; TMZ cytotoxicity assay; gamma -H2AX foci formation assay
• Mechanism Description: miR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT.

Disease Class: Glioblastoma [5]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Methylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Disease Class: Primary central nervous system lymphoma [6]

• Sensitive Disease: Primary central nervous system lymphoma [ICD-11: 2A8Z.0]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Raji cells; Brain; Homo sapiens (Human); CVCL_0511
• In Vitro Model: Primary central nervous system lymphoma; Spinal cord; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-370 was downregulated in PCNSL tissues, while MGMT was inversely overexpressed.TMZ sensitivity consistently correlated with the overexpression of miR-370 and inhibition of MGMT; miR-370 affected PCNSL cell proliferation and increased apoptosis via MGMT.

Disease Class: Primary central nervous system lymphoma [6]

• Sensitive Disease: Primary central nervous system lymphoma [ICD-11: 2A8Z.0]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Raji Burkitt cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our study described a new miR-370-mediated mechanism of MGMT regulation in PCNSL. We first showed that miR-370 was downregulated in PCNSL tissues, while MGMT was inversely overexpressed. It was also observed that miR-370 suppressed the expression of MGMT. Additionally, upregulation of miR-370 significantly increased TMZ sensitivity dependent of MGMT, thus suppressed Raji cell proliferation and induced apoptosis in vitro. These results suggest that miR-370 is a potential target in PCNSL treatment.

Vincristine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Malignant glioma [1]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Resistant Drug: Vincristine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.60E-01; Fold-change: -2.72E-02; Z-score: -5.98E-02
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.62E-01; Fold-change: -2.40E-01; Z-score: -6.41E-01
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.65E-01; Fold-change: 2.48E-01; Z-score: 4.03E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.61E-03; Fold-change: 1.09E+00; Z-score: 1.61E+00

References

• Ref 1: In vitro drug response and molecular markers associated with drug resistance in malignant gliomas .Clin Cancer Res. 2006 Aug 1;12(15):4523-32. doi: 10.1158/1078-0432.CCR-05-1830. 10.1158/1078-0432.CCR-05-1830
• Ref 2: LncRNA-XIST interacts with miR-29c to modulate the chemoresistance of glioma cell to TMZ through DNA mismatch repair pathway. Biosci Rep. 2017 Sep 7;37(5):BSR20170696. doi: 10.1042/BSR20170696. Print 2017 Oct 31.
• Ref 3: Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression. Sci Rep. 2016 Sep 6;6:32972. doi: 10.1038/srep32972.
• Ref 4: MiR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT. J Neurooncol. 2017 May;133(1):59-68. doi: 10.1007/s11060-017-2425-9. Epub 2017 Apr 19.
• Ref 5: Long noncoding RNA MALAT1 knockdown reverses chemoresistance to temozolomide via promoting microRNA-101 in glioblastoma. Cancer Med. 2018 Apr;7(4):1404-1415. doi: 10.1002/cam4.1384. Epub 2018 Feb 26.
• Ref 6: miR-370 Sensitizes TMZ Response Dependent of MGMT Status in Primary Central Nervous System Lymphoma .Pathol Oncol Res. 2020 Apr;26(2):707-714. doi: 10.1007/s12253-019-00605-4. Epub 2019 Feb 2. 10.1007/s12253-019-00605-4