Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4H6RKW)

• DOT Name: Dual specificity protein phosphatase 6 (DUSP6)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Dual specificity protein phosphatase PYST1; Mitogen-activated protein kinase phosphatase 3; MAP kinase phosphatase 3; MKP-3
• Gene Name: DUSP6
• Related Disease:
  Carcinoma
  Lung adenocarcinoma
  Adult glioblastoma
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colitis
  Colorectal neoplasm
  Depression
  Endometrial cancer
  Endometrial carcinoma
  Endometriosis
  Endometrium adenocarcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Hepatitis C virus infection
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Myocardial ischemia
  Nasopharyngeal carcinoma
  Obesity
  Ovarian neoplasm
  Pancreatic cancer
  Pancreatitis
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Triple negative breast cancer
  Gastric cancer
  Mood disorder
  Neuralgia
  Stomach cancer
  Hypogonadotropic hypogonadism
  Kallmann syndrome
  Neuroblastoma
  Undifferentiated carcinoma
  Advanced cancer
  Chronic obstructive pulmonary disease
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Hypogonadotropic hypogonadism 19 with or without anosmia
  Melanoma
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate carcinoma
• UniProt ID: DUS6_HUMAN
• PDB ID: 1HZM; 1MKP
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF00581
• Sequence:
  MIDTLRPVPFASEMAISKTVAWLNEQLELGNERLLLMDCRPQELYESSHIESAINVAIPG
  IMLRRLQKGNLPVRALFTRGEDRDRFTRRCGTDTVVLYDESSSDWNENTGGESVLGLLLK
  KLKDEGCRAFYLEGGFSKFQAEFSLHCETNLDGSCSSSSPPLPVLGLGGLRISSDSSSDI
  ESDLDRDPNSATDSDGSPLSNSQPSFPVEILPFLYLGCAKDSTNLDVLEEFGIKYILNVT
  PNLPNLFENAGEFKYKQIPISDHWSQNLSQFFPEAISFIDEARGKNCGVLVHCLAGISRS
  VTVTVAYLMQKLNLSMNDAYDIVKMKKSNISPNFNFMGQLLDFERTLGLSSPCDNRVPAQ
  QLYFTTPSNQNVYQVDSLQST
• Function: Inactivates MAP kinases. Has a specificity for the ERK family. Plays an important role in alleviating chronic postoperative pain. Necessary for the normal dephosphorylation of the long-lasting phosphorylated forms of spinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery, which drives the resolution of acute postoperative allodynia. Also important for dephosphorylation of MAPK1/3 in local wound tissue, which further contributes to resolution of acute pain. Promotes cell differentiation by regulating MAPK1/MAPK3 activity and regulating the expression of AP1 transcription factors.
• Tissue Specificity: Expressed in keratinocytes (at protein level).
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Transcriptio.l misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway:
  ERKs are inactivated (R-HSA-202670)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signaling by MAPK mutants (R-HSA-9652817)
  RAF-independent MAPK1/3 activation (R-HSA-112409)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Posttranslational Modification	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Posttranslational Modification	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Colitis	DISAF7DD	Strong	Biomarker	[8]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[8]
Depression	DIS3XJ69	Strong	Biomarker	[9]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[10]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[10]
Endometriosis	DISX1AG8	Strong	Altered Expression	[11]
Endometrium adenocarcinoma	DISY6744	Strong	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[13]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[14]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[15]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[15]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[15]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[13]
Obesity	DIS47Y1K	Strong	Genetic Variation	[17]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[18]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[19]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[20]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[21]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[21]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[22]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[23]
Gastric cancer	DISXGOUK	moderate	Biomarker	[24]
Mood disorder	DISLVMWO	moderate	Biomarker	[25]
Neuralgia	DISWO58J	moderate	Biomarker	[26]
Stomach cancer	DISKIJSX	moderate	Biomarker	[24]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[27]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[27]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[28]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[29]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[30]
Hypogonadotropic hypogonadism 19 with or without anosmia	DISZ5RJ5	Limited	Autosomal dominant	[31]
Melanoma	DIS1RRCY	Limited	Biomarker	[32]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[33]
Prostate cancer	DISF190Y	Limited	Biomarker	[34]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[34]

46 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 Dual specificity protein phosphatase 6 (DUSP6).	[35]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[40]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[41]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[42]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[43]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[44]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dual specificity protein phosphatase 6 (DUSP6).	[45]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[46]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[47]
Marinol	DM70IK5	Approved	Marinol increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[48]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[49]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Dual specificity protein phosphatase 6 (DUSP6).	[50]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[51]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dual specificity protein phosphatase 6 (DUSP6).	[45]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[52]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[53]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[54]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[55]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[56]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[57]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[58]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[59]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[60]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[61]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[62]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[63]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[64]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[65]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[66]
T83193	DMHO29Y	Patented	T83193 decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[67]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[68]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Dual specificity protein phosphatase 6 (DUSP6).	[69]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[70]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[71]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[72]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[73]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[74]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[75]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[76]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[77]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[78]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of Dual specificity protein phosphatase 6 (DUSP6).	[67]

References

• [1] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [2] Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells.Elife. 2018 Nov 26;7:e33718. doi: 10.7554/eLife.33718.
• [3] Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas.Oncogene. 2011 Sep 1;30(35):3813-20. doi: 10.1038/onc.2011.99. Epub 2011 Apr 18.
• [4] Promoter DNA hypermethylation - Implications for Alzheimer's disease.Neurosci Lett. 2019 Oct 15;711:134403. doi: 10.1016/j.neulet.2019.134403. Epub 2019 Jul 24.
• [5] Ras and TGF- signaling enhance cancer progression by promoting the Np63 transcriptional program.Sci Signal. 2016 Aug 23;9(442):ra84. doi: 10.1126/scisignal.aag3232.
• [6] Differential Roles for DUSP Family Members in Epithelial-to-Mesenchymal Transition and Cancer Stem Cell Regulation in Breast Cancer.PLoS One. 2016 Feb 9;11(2):e0148065. doi: 10.1371/journal.pone.0148065. eCollection 2016.
• [7] Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance.Cancer Res. 2006 Jun 1;66(11):5950-9. doi: 10.1158/0008-5472.CAN-05-3243.
• [8] Dual-specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis.J Cell Physiol. 2019 May;234(5):6731-6745. doi: 10.1002/jcp.27420. Epub 2018 Oct 1.
• [9] Electroconvulsive seizures increase the expression of MAP kinase phosphatases in limbic regions of rat brain.Neuropsychopharmacology. 2005 Feb;30(2):360-71. doi: 10.1038/sj.npp.1300588.
• [10] Dusp6 inhibits epithelial-mesenchymal transition in endometrial adenocarcinoma via ERK signaling pathway.Radiol Oncol. 2019 Sep 24;53(3):307-315. doi: 10.2478/raon-2019-0034.
• [11] Effect of FGF2 on the activity of SPRYs/DUSP6/ERK signaling pathway in endometrial glandular epithelial cells of endometriosis.Eur Rev Med Pharmacol Sci. 2018 Mar;22(6):1554-1568. doi: 10.26355/eurrev_201803_14560.
• [12] Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes.Oncotarget. 2019 May 21;10(36):3315-3327. eCollection 2019 May 21.
• [13] Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype.Int J Cancer. 2012 Jan 1;130(1):83-95. doi: 10.1002/ijc.25970. Epub 2011 Apr 20.
• [14] Protection of CD4+ T cells from hepatitis C virus infection-associated senescence via Np63-miR-181a-Sirt1 pathway.J Leukoc Biol. 2016 Nov;100(5):1201-1211. doi: 10.1189/jlb.5A0316-119RR. Epub 2016 Jun 27.
• [15] Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese.J Cancer Res Ther. 2018;14(Supplement):S72-S78. doi: 10.4103/0973-1482.172108.
• [16] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [17] Dual specificity phosphatase 6 deficiency is associated with impaired systemic glucose tolerance and reversible weight retardation in mice.PLoS One. 2017 Sep 5;12(9):e0183488. doi: 10.1371/journal.pone.0183488. eCollection 2017.
• [18] Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells.Carcinogenesis. 2008 Sep;29(9):1742-50. doi: 10.1093/carcin/bgn167. Epub 2008 Jul 16.
• [19] Haloperidol induces demethylation and expression of the dual specificity phosphatase 6 gene in MIA PaCa-2 human pancreatic cancer cells.Life Sci. 2012 Dec 17;91(25-26):1317-22. doi: 10.1016/j.lfs.2012.10.002. Epub 2012 Oct 12.
• [20] Map kinase phosphatases (MKP's) are early responsive genes during induction of cerulein hyperstimulation pancreatitis.Biochem Biophys Res Commun. 2000 Sep 24;276(2):680-5. doi: 10.1006/bbrc.2000.3530.
• [21] DUSP5 and DUSP6, two ERK specific phosphatases, are markers of a higher MAPK signaling activation in BRAF mutated thyroid cancers.PLoS One. 2017 Sep 14;12(9):e0184861. doi: 10.1371/journal.pone.0184861. eCollection 2017.
• [22] BRAF-Oncogene-Induced Senescence and the Role of Thyroid-Stimulating Hormone Signaling in the Progression of Papillary Thyroid Carcinoma.Horm Cancer. 2018 Feb;9(1):1-11. doi: 10.1007/s12672-017-0315-4. Epub 2017 Dec 5.
• [23] Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer.Int J Mol Sci. 2019 Jun 24;20(12):3080. doi: 10.3390/ijms20123080.
• [24] Pharmacological inhibition of DUSP6 suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance.Cancer Lett. 2018 Jan 1;412:243-255. doi: 10.1016/j.canlet.2017.10.007. Epub 2017 Oct 16.
• [25] Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler.Mol Psychiatry. 2000 Sep;5(5):461, 489-94.
• [26] Intrathecal injection of dexmedetomidine ameliorates chronic neuropathic pain via the modulation of MPK3/ERK1/2 in a mouse model of chronic neuropathic pain.Neurol Res. 2019 Dec;41(12):1059-1068. doi: 10.1080/01616412.2019.1672391. Epub 2019 Oct 4.
• [27] Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008.
• [28] The testosterone metabolite 3-androstanediol inhibits oxidative stress-induced ERK phosphorylation and neurotoxicity in SH-SY5Y cells through an MKP3/DUSP6-dependent mechanism.Neurosci Lett. 2019 Mar 23;696:60-66. doi: 10.1016/j.neulet.2018.12.012. Epub 2018 Dec 12.
• [29] Long non-coding RNA TUG1 promotes airway remodelling by suppressing the miR-145-5p/DUSP6 axis in cigarette smoke-induced COPD.J Cell Mol Med. 2019 Nov;23(11):7200-7209. doi: 10.1111/jcmm.14389. Epub 2019 Sep 26.
• [30] Tripartite motif-containing protein 7 regulates hepatocellular carcinoma cell proliferation via the DUSP6/p38 pathway.Biochem Biophys Res Commun. 2019 Apr 16;511(4):889-895. doi: 10.1016/j.bbrc.2019.02.001. Epub 2019 Mar 5.
• [31] DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem. 2008 Nov 7;283(45):31246-55. doi: 10.1074/jbc.M806085200. Epub 2008 Aug 27.
• [32] ATM Dependent DUSP6 Modulation of p53 Involved in Synergistic Targeting of MAPK and p53 Pathways with Trametinib and MDM2 Inhibitors in Cutaneous Melanoma.Cancers (Basel). 2018 Dec 20;11(1):3. doi: 10.3390/cancers11010003.
• [33] Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells.J Biol Chem. 2005 Oct 28;280(43):36013-8. doi: 10.1074/jbc.M508027200. Epub 2005 Aug 26.
• [34] Dual specificity phosphatase 6 suppresses the growth and metastasis of prostate cancer cells.Mol Med Rep. 2014 Dec;10(6):3052-8. doi: 10.3892/mmr.2014.2575. Epub 2014 Sep 18.
• [35] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [36] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [37] The retinoid anticancer signal: mechanisms of target gene regulation. Br J Cancer. 2005 Aug 8;93(3):310-8. doi: 10.1038/sj.bjc.6602700.
• [38] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance. Oncogene. 2012 May 10;31(19):2412-22. doi: 10.1038/onc.2011.426. Epub 2011 Sep 26.
• [42] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [43] 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.
• [44] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [45] 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.
• [46] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [47] The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-186.
• [48] Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway. Blood. 2005 Feb 1;105(3):1214-21. doi: 10.1182/blood-2004-03-1182. Epub 2004 Sep 28.
• [49] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [50] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [51] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [52] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [53] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [54] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [55] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [56] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [57] Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2076-81. doi: 10.1073/pnas.1011936108. Epub 2011 Jan 18.
• [58] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [59] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [60] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [61] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [62] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [63] 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.
• [64] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [65] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [66] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [67] Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair. Mutat Res. 2007 Mar 1;616(1-2):60-9. doi: 10.1016/j.mrfmmm.2006.11.022. Epub 2006 Dec 18.
• [68] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [69] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [70] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [71] 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.
• [72] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [73] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [74] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [75] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [76] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [77] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [78] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.