Details of Drug Off-Target (DOT)

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

• DOT Name: Proline-, glutamic acid- and leucine-rich protein 1 (PELP1)
• Synonyms: Modulator of non-genomic activity of estrogen receptor; Transcription factor HMX3
• Gene Name: PELP1
• Related Disease:
  Adenocarcinoma
  Lung carcinoma
  Precancerous condition
  Squamous cell carcinoma
  Adrenocortical carcinoma
  Androgen insensitivity syndrome
  Aplasia cutis congenita
  Aromatase excess syndrome
  Bone osteosarcoma
  Breast carcinoma
  Carcinoma
  Corpus callosum, agenesis of
  Ductal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glucocorticoid resistance
  Lung cancer
  Male infertility
  Malignant tumor of adrenal cortex
  Metastatic malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Rheumatoid arthritis
  Stomach cancer
  Ductal breast carcinoma in situ
  Invasive breast carcinoma
  Renal cell carcinoma
  Advanced cancer
  Estrogen-receptor positive breast cancer
  Endometrium neoplasm
  Triple negative breast cancer
• UniProt ID: PELP1_HUMAN
• PDB ID: 7UWF; 8FL2; 8FL3; 8FL4
• Pfam ID: PF08166 ; PF08167
• Sequence:
  MAAAVLSGPSAGSAAGVPGGTGGLSAVSSGPRLRLLLLESVSGLLQPRTGSAVAPVHPPN
  RSAPHLPGLMCLLRLHGSVGGAQNLSALGALVSLSNARLSSIKTRFEGLCLLSLLVGESP
  TELFQQHCVSWLRSIQQVLQTQDPPATMELAVAVLRDLLRYAAQLPALFRDISMNHLPGL
  LTSLLGLRPECEQSALEGMKACMTYFPRACGSLKGKLASFFLSRVDALSPQLQQLACECY
  SRLPSLGAGFSQGLKHTESWEQELHSLLASLHTLLGALYEGAETAPVQNEGPGVEMLLSS
  EDGDAHVLLQLRQRFSGLARCLGLMLSSEFGAPVSVPVQEILDFICRTLSVSSKNISLHG
  DGPLRLLLLPSIHLEALDLLSALILACGSRLLRFGILIGRLLPQVLNSWSIGRDSLSPGQ
  ERPYSTVRTKVYAILELWVQVCGASAGMLQGGASGEALLTHLLSDISPPADALKLRSPRG
  SPDGSLQTGKPSAPKKLKLDVGEAMAPPSHRKGDSNANSDVCAAALRGLSRTILMCGPLI
  KEETHRRLHDLVLPLVMGVQQGEVLGSSPYTSSRCRRELYCLLLALLLAPSPRCPPPLAC
  ALQAFSLGQREDSLEVSSFCSEALVTCAALTHPRVPPLQPMGPTCPTPAPVPPPEAPSPF
  RAPPFHPPGPMPSVGSMPSAGPMPSAGPMPSAGPVPSARPGPPTTANHLGLSVPGLVSVP
  PRLLPGPENHRAGSNEDPILAPSGTPPPTIPPDETFGGRVPRPAFVHYDKEEASDVEISL
  ESDSDDSVVIVPEGLPPLPPPPPSGATPPPIAPTGPPTASPPVPAKEEPEELPAAPGPLP
  PPPPPPPPVPGPVTLPPPQLVPEGTPGGGGPPALEEDLTVININSSDEEEEEEEEEEEEE
  EEEEEEEEDFEEEEEDEEEYFEEEEEEEEEFEEEFEEEEGELEEEEEEEDEEEEEELEEV
  EDLEFGTAGGEVEEGAPPPPTLPPALPPPESPPKVQPEPEPEPGLLLEVEEPGTEEERGA
  DTAPTLAPEALPSQGEVEREGESPAAGPPPQELVEEEPSAPPTLLEEETEDGSDKVQPPP
  ETPAEEEMETETEAEALQEKEQDDTAAMLADFIDCPPDDEKPPPPTEPDS
• Function: Coactivator of estrogen receptor-mediated transcription and a corepressor of other nuclear hormone receptors and sequence-specific transcription factors. Plays a role in estrogen receptor (ER) genomic activity when present in the nuclear compartment by activating the ER target genes in a hormonal stimulation dependent manner. Can facilitate ER non-genomic signaling via SRC and PI3K interaction in the cytosol. Plays a role in E2-mediated cell cycle progression by interacting with RB1. May have important functional implications in ER/growth factor cross-talk. Interacts with several growth factor signaling components including EGFR and HRS. Functions as the key stabilizing component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes. Component of the PELP1 complex involved in the nucleolar steps of 28S rRNA maturation and the subsequent nucleoplasmic transit of the pre-60S ribosomal subunit. Regulates pre-60S association of the critical remodeling factor MDN1. May promote tumorigenesis via its interaction with and modulation of several oncogenes including SRC, PI3K, STAT3 and EGFR. Plays a role in cancer cell metastasis via its ability to modulate E2-mediated cytoskeleton changes and cell migration via its interaction with SRC and PI3K.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  PTK6 Expression (R-HSA-8849473)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[1]
Precancerous condition	DISV06FL	Definitive	Altered Expression	[2]
Squamous cell carcinoma	DISQVIFL	Definitive	Altered Expression	[1]
Adrenocortical carcinoma	DISZF4HX	Strong	Biomarker	[3]
Androgen insensitivity syndrome	DISUZBBO	Strong	Genetic Variation	[4]
Aplasia cutis congenita	DISMDAYM	Strong	Biomarker	[3]
Aromatase excess syndrome	DIS1N9UV	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[3]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[8]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Glucocorticoid resistance	DIS3HNXT	Strong	Genetic Variation	[13]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Male infertility	DISY3YZZ	Strong	Biomarker	[14]
Malignant tumor of adrenal cortex	DIS7E0I8	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[16]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[16]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[18]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[10]
Ductal breast carcinoma in situ	DISLCJY7	moderate	Altered Expression	[19]
Invasive breast carcinoma	DISANYTW	moderate	Biomarker	[2]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Disputed	Altered Expression	[15]
Estrogen-receptor positive breast cancer	DIS1H502	Disputed	Biomarker	[20]
Endometrium neoplasm	DIS6OS2L	Limited	Altered Expression	[21]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[26]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[27]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Proline-, glutamic acid- and leucine-rich protein 1 (PELP1).	[28]

References

• [1] Increased expression of proline-, glutamic acid- and leucine-rich protein PELP1 in non-small cell lung cancer.Biomed Pharmacother. 2015 Jul;73:97-101. doi: 10.1016/j.biopha.2015.05.015. Epub 2015 Jun 1.
• [2] Cytoplasmic Localization of Proline, Glutamic Acid, Leucine-rich Protein 1 (PELP1) Induces Breast Epithelial Cell Migration through Up-regulation of Inhibitor of B Kinase and Inflammatory Cross-talk with Macrophages.J Biol Chem. 2017 Jan 6;292(1):339-350. doi: 10.1074/jbc.M116.739847. Epub 2016 Nov 23.
• [3] Role of Scaffold Protein Proline-, Glutamic Acid-, and Leucine-Rich Protein 1 (PELP1) in the Modulation of Adrenocortical Cancer Cell Growth.Cells. 2017 Nov 7;6(4):42. doi: 10.3390/cells6040042.
• [4] Androgen receptor mutations identified in prostate cancer and androgen insensitivity syndrome display aberrant ART-27 coactivator function.Mol Endocrinol. 2005 Sep;19(9):2273-82. doi: 10.1210/me.2005-0134. Epub 2005 May 26.
• [5] Modulation of in situ estrogen synthesis by proline-, glutamic acid-, and leucine-rich protein-1: potential estrogen receptor autocrine signaling loop in breast cancer cells.Mol Endocrinol. 2008 Mar;22(3):649-64. doi: 10.1210/me.2007-0350. Epub 2007 Dec 13.
• [6] Cloning and functional characterization of PELP1/MNAR promoter.Gene. 2004 Apr 14;330:115-22. doi: 10.1016/j.gene.2004.01.011.
• [7] The Clinical Value of PELP1 for Breast Cancer: A Comparison with Multiple Cancers and Analysis in Breast Cancer Subtypes.Cancer Res Treat. 2019 Apr;51(2):706-717. doi: 10.4143/crt.2018.316. Epub 2018 Aug 23.
• [8] Novel estrogen receptor coactivator PELP1/MNAR gene and ERbeta expression in salivary duct adenocarcinoma: potential therapeutic targets.Hum Pathol. 2005 Jun;36(6):670-5. doi: 10.1016/j.humpath.2005.03.016.
• [9] PELP1/MNAR suppression inhibits proliferation and metastasis of endometrial carcinoma cells.Oncol Rep. 2012 Dec;28(6):2035-42. doi: 10.3892/or.2012.2038. Epub 2012 Sep 17.
• [10] PELP1 is a novel oncogene in gastric tumorigenesis and negatively regulated by miR-15 family microRNAs.Cancer Biomark. 2019;26(1):1-9. doi: 10.3233/CBM-182279.
• [11] Therapeutic targeting of PELP1 prevents ovarian cancer growth and metastasis.Clin Cancer Res. 2011 Apr 15;17(8):2250-9. doi: 10.1158/1078-0432.CCR-10-2718. Epub 2011 Mar 18.
• [12] Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis.Cancer Lett. 2019 May 28;450:22-31. doi: 10.1016/j.canlet.2019.02.014. Epub 2019 Feb 13.
• [13] A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities.J Clin Endocrinol Metab. 2014 May;99(5):E902-7. doi: 10.1210/jc.2013-3005. Epub 2014 Jan 31.
• [14] Increased expression of PELP1 in human sperm is correlated with decreased semen quality.Asian J Androl. 2018 Sep-Oct;20(5):425-431. doi: 10.4103/aja.aja_11_18.
• [15] Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer.Oncogene. 2014 Jul 10;33(28):3707-16. doi: 10.1038/onc.2013.332. Epub 2013 Aug 26.
• [16] Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover.Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6997-7002. doi: 10.1073/pnas.1304502110. Epub 2013 Apr 4.
• [17] Proline-, glutamic acid-, and leucine-rich protein-1/modulator of nongenomic activity of estrogen receptor enhances androgen receptor functions through LIM-only coactivator, four-and-a-half LIM-only protein 2.Mol Endocrinol. 2007 Mar;21(3):613-24. doi: 10.1210/me.2006-0269. Epub 2006 Dec 27.
• [18] Expression of cAMP response element binding protein (CREB)-binding protein (CBP) and the implication in retinoic acid-inducible transcription activation in human salivary gland adenocarcinoma cell line HSG.Endocr Res. 2003 Aug;29(3):277-89. doi: 10.1081/erc-120025035.
• [19] Oncogenic potential of the nuclear receptor coregulator proline-, glutamic acid-, leucine-rich protein 1/modulator of the nongenomic actions of the estrogen receptor.Cancer Res. 2007 Jun 1;67(11):5505-12. doi: 10.1158/0008-5472.CAN-06-3647.
• [20] Estrogens Correlate with PELP1 Expression in ER Positive Breast Cancer.PLoS One. 2015 Aug 6;10(8):e0134351. doi: 10.1371/journal.pone.0134351. eCollection 2015.
• [21] Deregulation of estrogen receptor coactivator proline-, glutamic acid-, and leucine-rich protein-1/modulator of nongenomic activity of estrogen receptor in human endometrial tumors.J Clin Endocrinol Metab. 2004 Dec;89(12):6130-8. doi: 10.1210/jc.2004-0909.
• [22] Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer.Cancer Res. 2016 Mar 15;76(6):1653-63. doi: 10.1158/0008-5472.CAN-15-2510. Epub 2016 Jan 29.
• [23] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [24] 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.
• [25] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [26] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [27] 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.
• [28] Identifying the estrogen receptor coactivator PELP1 in autophagosomes. Cancer Res. 2007 Sep 1;67(17):8164-71. doi: 10.1158/0008-5472.CAN-07-0038.
• [29] 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.
• [30] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.