Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7K8MTJ)

• DOT Name: Regulator of MON1-CCZ1 complex (RMC1)
• Synonyms: Colon cancer-associated protein Mic1; Mic-1; WD repeat-containing protein 98
• Gene Name: RMC1
• Related Disease:
  Glioma
  Adenoma
  Adult glioblastoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Benign prostatic hyperplasia
  Bladder cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Diabetic retinopathy
  Glioblastoma multiforme
  Liver cirrhosis
  Lung adenocarcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Pancreatic cancer
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Stomach cancer
  Stroke
  Ulcerative colitis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Castration-resistant prostate carcinoma
  Diabetic kidney disease
  Gastric cancer
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Methicillin-resistant staphylococci infection
  Bone osteosarcoma
  Cardiovascular disease
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Melanoma
  Obesity
  Osteosarcoma
  Parkinson disease
  T-cell acute lymphoblastic leukaemia
• UniProt ID: RMC1_HUMAN
• Pfam ID: PF07035 ; PF21029
• Sequence:
  MGEEDYYLELCERPVQFEKANPVNCVFFDEANKQVFAVRSGGATGVVVKGPDDRNPISFR
  MDDKGEVKCIKFSLENKILAVQRTSKTVDFCNFIPDNSQLEYTQECKTKNANILGFCWTS
  STEIVFITDQGIEFYQVLPEKRSLKLLKSHNLNVNWYMYCPESAVILLSTTVLENVLQPF
  HFRAGTMSKLPKFEIELPAAPKSTKPSLSERDIAMATIYGQLYVLFLRHHSRTSNSTGAE
  VVLYHLPREGACKKMHILKLNRTGKFALNVVDNLVVVHHQDTETSVIFDIKLRGEFDGSV
  TFHHPVLPARSIQPYQIPITGPAAVTSQSPVPCKLYSSSWIVFQPDIIISASQGYLWNLQ
  VKLEPIVNLLPDKGRLMDFLLQRKECKMVILSVCSQMLSESDRASLPVIATVFDKLNHEY
  KKYLDAEQSYAMAVEAGQSRSSPLLKRPVRTQAVLDQSDVYTHVLSAFVEKKEMPHKFVI
  AVLMEYIRSLNQFQIAVQHYLHELVIKTLVQHNLFYMLHQFLQYHVLSDSKPLACLLLSL
  ESFYPPAHQLSLDMLKRLSTANDEIVEVLLSKHQVLAALRFIRGIGGHDNISARKFLDAA
  KQTEDNMLFYTIFRFFEQRNQRLRGSPNFTPGEHCEEHVAFFKQIFGDQALMRPTTF
• Function: Componement of the CCZ1-MON1 RAB7A guanine exchange factor (GEF). Acts as a positive regulator of CCZ1-MON1A/B function necessary for endosomal/autophagic flux and efficient RAB7A localization.

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[5]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[6]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[7]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Cardiac failure	DISDC067	Strong	Biomarker	[10]
Colon cancer	DISVC52G	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[13]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[16]
Pancreatic cancer	DISJC981	Strong	Biomarker	[17]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[18]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[19]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[20]
Stroke	DISX6UHX	Strong	Genetic Variation	[21]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[22]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[7]
Castration-resistant prostate carcinoma	DISVGAE6	moderate	Biomarker	[23]
Diabetic kidney disease	DISJMWEY	moderate	Altered Expression	[24]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[25]
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[26]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[27]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[28]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[27]
Cardiovascular disease	DIS2IQDX	Limited	Biomarker	[29]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[30]
Lung cancer	DISCM4YA	Limited	Biomarker	[31]
Lung carcinoma	DISTR26C	Limited	Biomarker	[31]
Melanoma	DIS1RRCY	Limited	Biomarker	[32]
Obesity	DIS47Y1K	Limited	Altered Expression	[33]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[27]
Parkinson disease	DISQVHKL	Limited	Biomarker	[34]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Genetic Variation	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[40]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[41]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[45]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Regulator of MON1-CCZ1 complex (RMC1).	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Regulator of MON1-CCZ1 complex (RMC1).	[44]

References

• [1] Elevated levels of MIC-1/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome.Int J Cancer. 2009 Dec 1;125(11):2624-30. doi: 10.1002/ijc.24639.
• [2] Macrophage inhibitory cytokine-1/growth differentiation factor-15 as a predictor of colonic neoplasia.Aliment Pharmacol Ther. 2017 Aug;46(3):347-354. doi: 10.1111/apt.14156. Epub 2017 Jun 1.
• [3] A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood.Front Genet. 2018 Mar 23;9:97. doi: 10.3389/fgene.2018.00097. eCollection 2018.
• [4] Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages.Atherosclerosis. 2019 Feb;281:128-136. doi: 10.1016/j.atherosclerosis.2018.12.009. Epub 2018 Dec 19.
• [5] Association of NT-proBNP and GDF-15 with markers of a prothrombotic state in patients with atrial fibrillation off anticoagulation.Clin Res Cardiol. 2020 Apr;109(4):426-434. doi: 10.1007/s00392-019-01522-x. Epub 2019 Jul 6.
• [6] Relevance of MIC-1 in the Era of PSA as a Serum Based Predictor of Prostate Cancer: A Critical Evaluation.Sci Rep. 2017 Dec 4;7(1):16824. doi: 10.1038/s41598-017-17207-2.
• [7] Association of prostatic inflammation with down-regulation of macrophage inhibitory cytokine-1 gene in symptomatic benign prostatic hyperplasia.J Urol. 2004 Jun;171(6 Pt 1):2330-5. doi: 10.1097/01.ju.0000127760.87421.e9.
• [8] Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer.J Cell Physiol. 2010 Sep;224(3):626-35. doi: 10.1002/jcp.22196.
• [9] Macrophage inhibitory cytokine-1 transactivates ErbB family receptors via the activation of Src in SK-BR-3 human breast cancer cells.BMB Rep. 2010 Feb;43(2):91-6. doi: 10.5483/bmbrep.2010.43.2.091.
• [10] The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL.Nat Med. 2017 Oct;23(10):1215-1219. doi: 10.1038/nm.4393. Epub 2017 Aug 28.
• [11] Macrophage inhibitory cytokine-1 (MIC-1) and subsequent urokinase-type plasminogen activator mediate cell death responses by ribotoxic anisomycin in HCT-116 colon cancer cells.Biochem Pharmacol. 2009 Nov 1;78(9):1205-13. doi: 10.1016/j.bcp.2009.06.012. Epub 2009 Jun 18.
• [12] miR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress.Exp Eye Res. 2018 Mar;168:89-99. doi: 10.1016/j.exer.2017.11.006. Epub 2017 Nov 28.
• [13] Induction of MIC-1/growth differentiation factor-15 following bile duct injury.J Gastrointest Surg. 2003 Nov;7(7):901-5. doi: 10.1007/s11605-003-0037-5.
• [14] Ruthenium methylimidazole complexes induced apoptosis in lung cancer A549 cells through intrinsic mitochondrial pathway.Biochimie. 2012 Feb;94(2):345-53. doi: 10.1016/j.biochi.2011.07.025. Epub 2011 Jul 28.
• [15] The value of macrophage inhibitory cytokine-1 level in differentiating benign from malignant solitary pulmonary nodules.Clin Respir J. 2018 Apr;12(4):1473-1478. doi: 10.1111/crj.12693. Epub 2017 Sep 14.
• [16] Association between MIC-1 and Type 2 Diabetes: A Combined Analysis.Dis Markers. 2019 Nov 16;2019:7284691. doi: 10.1155/2019/7284691. eCollection 2019.
• [17] Macrophage inhibitory cytokine-1 versus carbohydrate antigen 19-9 as a biomarker for diagnosis of pancreatic cancer: A PRISMA-compliant meta-analysis of diagnostic accuracy studies.Medicine (Baltimore). 2018 Mar;97(9):e9994. doi: 10.1097/MD.0000000000009994.
• [18] Knockdown of macrophage inhibitory cytokine-1 in RPMI-8226 human multiple myeloma cells inhibits osteoclastic differentiation through inhibiting the RANKL-Erk1/2 signaling pathway.Mol Med Rep. 2016 Dec;14(6):5199-5204. doi: 10.3892/mmr.2016.5879. Epub 2016 Oct 24.
• [19] Biomarkers associated with cardiovascular disease in patients with early rheumatoid arthritis.PLoS One. 2019 Aug 5;14(8):e0220531. doi: 10.1371/journal.pone.0220531. eCollection 2019.
• [20] Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells.Carcinogenesis. 2008 Apr;29(4):704-12. doi: 10.1093/carcin/bgn031. Epub 2008 Feb 6.
• [21] Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9p21.3 region in patients with rheumatoid arthritis and cardiovascular disease.J Rheumatol. 2012 May;39(5):939-45. doi: 10.3899/jrheum.111336. Epub 2012 Apr 15.
• [22] Isothiocyanate-enriched moringa seed extract alleviates ulcerative colitis symptoms in mice.PLoS One. 2017 Sep 18;12(9):e0184709. doi: 10.1371/journal.pone.0184709. eCollection 2017.
• [23] Identification of candidate biomarkers of therapeutic response to docetaxel by proteomic profiling.Cancer Res. 2009 Oct 1;69(19):7696-703. doi: 10.1158/0008-5472.CAN-08-4901. Epub 2009 Sep 22.
• [24] Moringa Isothiocyanate Activates Nrf2: Potential Role in Diabetic Nephropathy.AAPS J. 2019 Feb 19;21(2):31. doi: 10.1208/s12248-019-0301-6.
• [25] Upregulation and secretion of macrophage inhibitory cytokine-1 (MIC-1) in gastric cancers.Clin Chim Acta. 2009 Mar;401(1-2):128-33. doi: 10.1016/j.cca.2008.12.008. Epub 2008 Dec 14.
• [26] Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma.BMC Cancer. 2014 Aug 8;14:578. doi: 10.1186/1471-2407-14-578.
• [27] Elevated circulating macrophage inhibitory cytokine 1 is a biological marker for the diagnosis and prognosis of osteosarcoma.Exp Ther Med. 2018 Dec;16(6):4803-4809. doi: 10.3892/etm.2018.6786. Epub 2018 Sep 21.
• [28] In vitro activity of ceftaroline and ceftobiprole against methicillin-resistant Staphylococcus aureus with decreased susceptibility to vancomycin isolated in paediatric patients.J Chemother. 2018 Oct-Dec;30(6-8):338-341. doi: 10.1080/1120009X.2018.1522473. Epub 2018 Oct 30.
• [29] The clinical impact of growth differentiation factor-15 in heart disease: A 2019 update.Crit Rev Clin Lab Sci. 2020 Mar;57(2):114-125. doi: 10.1080/10408363.2019.1678565. Epub 2019 Oct 30.
• [30] Circulating MIC-1/GDF15 is a complementary screening biomarker with CEA and correlates with liver metastasis and poor survival in colorectal cancer.Oncotarget. 2017 Apr 11;8(15):24892-24901. doi: 10.18632/oncotarget.15279.
• [31] A novel serum based biomarker panel has complementary ability to preclude presence of early lung cancer for low dose CT (LDCT).Oncotarget. 2017 Jul 11;8(28):45345-45355. doi: 10.18632/oncotarget.17477.
• [32] Macrophage inhibitory cytokine-1 regulates melanoma vascular development.Am J Pathol. 2010 Jun;176(6):2948-57. doi: 10.2353/ajpath.2010.090963. Epub 2010 Apr 29.
• [33] Diet-induced macrophage inhibitory cytokine 1 promotes prostate cancer progression.Endocr Relat Cancer. 2013 Dec 16;21(1):39-50. doi: 10.1530/ERC-13-0227. Print 2014 Feb.
• [34] GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson's Disease and Lewy Body Dementia.PLoS One. 2016 Mar 3;11(3):e0149349. doi: 10.1371/journal.pone.0149349. eCollection 2016.
• [35] A panel of irradiation-reduced hybrids selectively retaining human chromosome 11p13: their structure and use to purify the WAGR gene complex.Genomics. 1990 Jan;6(1):48-64. doi: 10.1016/0888-7543(90)90447-3.
• [36] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [37] 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.
• [38] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [39] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [40] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [41] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [42] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [43] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [44] 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.
• [45] 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.
• [46] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.