Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVPEI80)

• DOT Name: Protein MAL2 (MAL2)
• Gene Name: MAL2
• Related Disease:
  Breast cancer
  Carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Pancreatic cancer
  Renal cell carcinoma
  Neoplasm
  Thyroid gland papillary carcinoma
  Breast carcinoma
• UniProt ID: MAL2_HUMAN
• Pfam ID: PF01284
• Sequence:
  MSAGGASVPPPPNPAVSFPPPRVTLPAGPDILRTYSGAFVCLEILFGGLVWILVASSNVP
  LPLLQGWVMFVSVTAFFFSLLFLGMFLSGMVAQIDANWNFLDFAYHFTVFVFYFGAFLLE
  AAATSLHDLHCNTTITGQPLLSDNQYNINVAASIFAFMTTACYGCSLGLALRRWRP
• Function: Member of the machinery of polarized transport. Required for the indirect transcytotic route at the step of the egress of the transcytosing cargo from perinuclear endosomes in order for it to travel to the apical surface via a raft-dependent pathway.
• Tissue Specificity: Predominantly expressed in kidney, lung, and liver. Also found in thyroid gland, stomach and, at lower levels in testis and small intestine.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[6]
Pancreatic cancer	DISJC981	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Biomarker	[7]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[1]

16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein MAL2 (MAL2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein MAL2 (MAL2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein MAL2 (MAL2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein MAL2 (MAL2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein MAL2 (MAL2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein MAL2 (MAL2).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein MAL2 (MAL2).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein MAL2 (MAL2).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Protein MAL2 (MAL2).	[16]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Protein MAL2 (MAL2).	[17]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Protein MAL2 (MAL2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein MAL2 (MAL2).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein MAL2 (MAL2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein MAL2 (MAL2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein MAL2 (MAL2).	[24]
Choline	DM5D9YK	Investigative	Choline affects the expression of Protein MAL2 (MAL2).	[25]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein MAL2 (MAL2).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein MAL2 (MAL2).	[22]

References

• [1] MAL2 promotes proliferation, migration, and invasion through regulating epithelial-mesenchymal transition in breast cancer cell lines.Biochem Biophys Res Commun. 2018 Oct 2;504(2):434-439. doi: 10.1016/j.bbrc.2018.08.187. Epub 2018 Sep 6.
• [2] Expression and distribution of MAL2, an essential element of the machinery for basolateral-to-apical transcytosis, in human thyroid epithelial cells.Endocrinology. 2004 Feb;145(2):1011-6. doi: 10.1210/en.2003-0652. Epub 2003 Oct 23.
• [3] Gene expression profiling separates chromophobe renal cell carcinoma from oncocytoma and identifies vesicular transport and cell junction proteins as differentially expressed genes.Clin Cancer Res. 2006 Dec 1;12(23):6937-45. doi: 10.1158/1078-0432.CCR-06-1268.
• [4] The four-transmembrane protein MAL2 and tumor protein D52 (TPD52) are highly expressed in colorectal cancer and correlated with poor prognosis.PLoS One. 2017 May 31;12(5):e0178515. doi: 10.1371/journal.pone.0178515. eCollection 2017.
• [5] Dynamics of MAL2 during glycosylphosphatidylinositol-anchored protein transcytotic transport to the apical surface of hepatoma HepG2 cells.Traffic. 2006 Jan;7(1):61-73. doi: 10.1111/j.1600-0854.2005.00361.x.
• [6] MAL2 expression predicts distant metastasis and short survival in pancreatic cancer.Surgery. 2013 Sep;154(3):573-82. doi: 10.1016/j.surg.2013.03.010. Epub 2013 Jul 19.
• [7] MiR-129 regulates growth and invasion by targeting MAL2 in papillary thyroid carcinoma.Biomed Pharmacother. 2018 Sep;105:1072-1078. doi: 10.1016/j.biopha.2018.06.050. Epub 2018 Jun 19.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [18] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [25] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.