Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPNQXF3)

• DOT Name: Podocalyxin (PODXL)
• Synonyms: GCTM-2 antigen; Gp200; Podocalyxin-like protein 1; PC; PCLP-1
• Gene Name: PODXL
• Related Disease:
  Wilms tumor
  Adenocarcinoma
  Advanced cancer
  Arteriosclerosis
  Astrocytoma
  Atherosclerosis
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiovascular disease
  Carotid artery disease
  Childhood kidney Wilms tumor
  Cholangiocarcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Familial nephrotic syndrome
  Glioblastoma multiforme
  High blood pressure
  Melanoma
  Neoplasm
  Nephropathy
  Nephrotic syndrome
  Pancreatic cancer
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Thrombosis
  Type-1/2 diabetes
  Autosomal recessive juvenile Parkinson disease 2
  Focal segmental glomerulosclerosis
  Gastric cancer
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Non-insulin dependent diabetes
  Pancreatic ductal carcinoma
  Stomach cancer
  Atypical juvenile parkinsonism
  Young-onset Parkinson disease
  Bladder cancer
  Kidney failure
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lupus nephritis
  Prostate neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: PODXL_HUMAN
• Pfam ID: PF06365
• Sequence:
  MRCALALSALLLLLSTPPLLPSSPSPSPSPSQNATQTTTDSSNKTAPTPASSVTIMATDT
  AQQSTVPTSKANEILASVKATTLGVSSDSPGTTTLAQQVSGPVNTTVARGGGSGNPTTTI
  ESPKSTKSADTTTVATSTATAKPNTTSSQNGAEDTTNSGGKSSHSVTTDLTSTKAEHLTT
  PHPTSPLSPRQPTSTHPVATPTSSGHDHLMKISSSSSTVAIPGYTFTSPGMTTTLLETVF
  HHVSQAGLELLTSGDLPTLASQSAGITASSVISQRTQQTSSQMPASSTAPSSQETVQPTS
  PATALRTPTLPETMSSSPTAASTTHRYPKTPSPTVAHESNWAKCEDLETQTQSEKQLVLN
  LTGNTLCAGGASDEKLISLICRAVKATFNPAQDKCGIRLASVPGSQTVVVKEITIHTKLP
  AKDVYERLKDKWDELKEAGVSDMKLGDQGPPEEAEDRFSMPLIITIVCMASFLLLVAALY
  GCCHQRLSQRKDQQRLTEELQTVENGYHDNPTLEVMETSSEMQEKKVVSLNGELGDSWIV
  PLDNLTKDDLDEEEDTHL
• Function: Involved in the regulation of both adhesion and cell morphology and cancer progression. Functions as an anti-adhesive molecule that maintains an open filtration pathway between neighboring foot processes in the podocyte by charge repulsion. Acts as a pro-adhesive molecule, enhancing the adherence of cells to immobilized ligands, increasing the rate of migration and cell-cell contacts in an integrin-dependent manner. Induces the formation of apical actin-dependent microvilli. Involved in the formation of a preapical plasma membrane subdomain to set up initial epithelial polarization and the apical lumen formation during renal tubulogenesis. Plays a role in cancer development and aggressiveness by inducing cell migration and invasion through its interaction with the actin-binding protein EZR. Affects EZR-dependent signaling events, leading to increased activities of the MAPK and PI3K pathways in cancer cells.
• Tissue Specificity: Glomerular epithelium cell (podocyte).
• KEGG Pathway: Salmonella infection (hsa05132)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Wilms tumor	DISB6T16	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Astrocytoma	DISL3V18	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
B-cell neoplasm	DISVY326	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[4]
Carotid artery disease	DISLRVLT	Strong	Biomarker	[8]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Biomarker	[1]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Familial nephrotic syndrome	DISADF8G	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[14]
High blood pressure	DISY2OHH	Strong	Altered Expression	[4]
Melanoma	DIS1RRCY	Strong	Altered Expression	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Nephropathy	DISXWP4P	Strong	Biomarker	[17]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[18]
Pancreatic cancer	DISJC981	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[19]
Prostate cancer	DISF190Y	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Thrombosis	DIS2TXP8	Strong	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[4]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	moderate	Genetic Variation	[21]
Focal segmental glomerulosclerosis	DISJNHH0	moderate	Genetic Variation	[22]
Gastric cancer	DISXGOUK	moderate	Biomarker	[23]
Matthew-Wood syndrome	DISA7HR7	moderate	Altered Expression	[24]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Altered Expression	[17]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[24]
Stomach cancer	DISKIJSX	moderate	Biomarker	[23]
Atypical juvenile parkinsonism	DISYXFE3	Supportive	Autosomal recessive	[21]
Young-onset Parkinson disease	DIS05LFS	Supportive	Autosomal recessive	[21]
Bladder cancer	DISUHNM0	Limited	Biomarker	[25]
Kidney failure	DISOVQ9P	Limited	Genetic Variation	[22]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[26]
Lung cancer	DISCM4YA	Limited	Altered Expression	[26]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[26]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[27]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[20]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[25]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[25]

26 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 Podocalyxin (PODXL).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Podocalyxin (PODXL).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Podocalyxin (PODXL).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Podocalyxin (PODXL).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Podocalyxin (PODXL).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Podocalyxin (PODXL).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Podocalyxin (PODXL).	[34]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Podocalyxin (PODXL).	[35]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Podocalyxin (PODXL).	[36]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Podocalyxin (PODXL).	[37]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Podocalyxin (PODXL).	[37]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Podocalyxin (PODXL).	[38]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Podocalyxin (PODXL).	[39]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Podocalyxin (PODXL).	[40]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Podocalyxin (PODXL).	[28]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Podocalyxin (PODXL).	[41]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Podocalyxin (PODXL).	[42]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Podocalyxin (PODXL).	[43]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Podocalyxin (PODXL).	[43]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Podocalyxin (PODXL).	[43]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Podocalyxin (PODXL).	[44]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Podocalyxin (PODXL).	[28]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Podocalyxin (PODXL).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Podocalyxin (PODXL).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Podocalyxin (PODXL).	[47]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Podocalyxin (PODXL).	[48]

1 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 Podocalyxin (PODXL).	[45]

References

• [1] Application of miR-193a/WT1/PODXL axis to estimate risk and prognosis of idiopathic membranous nephropathy.Ren Fail. 2019 Nov;41(1):704-717. doi: 10.1080/0886022X.2019.1642210.
• [2] A Direct Podocalyxin-Dynamin-2 Interaction Regulates Cytoskeletal Dynamics to Promote Migration and Metastasis in Pancreatic Cancer Cells.Cancer Res. 2019 Jun 1;79(11):2878-2891. doi: 10.1158/0008-5472.CAN-18-3369. Epub 2019 Apr 11.
• [3] Next-generation sequencing reveals hsa_circ_0058092 being a potential oncogene candidate involved in gastric cancer.Gene. 2020 Feb 5;726:144176. doi: 10.1016/j.gene.2019.144176. Epub 2019 Oct 26.
• [4] Serum podocalyxin levels correlate with carotid intima media thickness, implicating its role as a novel biomarker for atherosclerosis.Sci Rep. 2018 Jan 10;8(1):245. doi: 10.1038/s41598-017-18647-6.
• [5] Spermassociated antigen 9 promotes astrocytoma cell invasion through the upregulation of podocalyxin.Mol Med Rep. 2014 Jul;10(1):417-22. doi: 10.3892/mmr.2014.2168. Epub 2014 Apr 24.
• [6] Podocalyxin promotes proliferation and survival in mature B-cell non-Hodgkin lymphoma cells.Oncotarget. 2017 Sep 27;8(59):99722-99739. doi: 10.18632/oncotarget.21283. eCollection 2017 Nov 21.
• [7] Podocalyxin enhances breast tumor growth and metastasis and is a target for monoclonal antibody therapy.Breast Cancer Res. 2015 Mar 27;17(1):46. doi: 10.1186/s13058-015-0562-7.
• [8] Diminished thrombogenic responses by deletion of the Podocalyxin Gene in mouse megakaryocytes.PLoS One. 2011;6(10):e26025. doi: 10.1371/journal.pone.0026025. Epub 2011 Oct 7.
• [9] Podocalyxin-like protein 1 expression is useful to differentiate pancreatic ductal adenocarcinomas from adenocarcinomas of the biliary and gastrointestinal tracts.Hum Pathol. 2007 Feb;38(2):359-64. doi: 10.1016/j.humpath.2006.08.025. Epub 2006 Nov 29.
• [10] Podocalyxin-Like Protein 1 Regulates TAZ Signaling and Stemness Properties in Colon Cancer.Int J Mol Sci. 2017 Sep 23;18(10):2047. doi: 10.3390/ijms18102047.
• [11] Extracellular and transmembrane region of a podocalyxin-like protein 1 fragment identified from colon cancer cell lines.Cell Biol Int. 2007 Dec;31(12):1518-24. doi: 10.1016/j.cellbi.2007.06.017. Epub 2007 Jul 15.
• [12] Identification of LEA, a podocalyxin-like glycoprotein, as a predictor for the progression of colorectal cancer.Cancer Med. 2018 Oct;7(10):5155-5166. doi: 10.1002/cam4.1765. Epub 2018 Sep 12.
• [13] Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.Kidney Int. 2017 Apr;91(4):937-947. doi: 10.1016/j.kint.2016.10.013. Epub 2017 Jan 20.
• [14] Podocalyxin promotes glioblastoma multiforme cell invasion and proliferation by inhibiting angiotensin-(1-7)/Mas signaling.Oncol Rep. 2015 May;33(5):2583-91. doi: 10.3892/or.2015.3813. Epub 2015 Feb 20.
• [15] Inhibition of p38/MK2 Signaling Prevents Vascular Invasion of Melanoma.J Invest Dermatol. 2020 Apr;140(4):878-890.e5. doi: 10.1016/j.jid.2019.08.451. Epub 2019 Oct 14.
• [16] Podocalyxin-like, targeted by miR-138, promotes colorectal cancer cell proliferation, migration, invasion and EMT.Eur Rev Med Pharmacol Sci. 2018 Dec;22(24):8664-8674. doi: 10.26355/eurrev_201812_16631.
• [17] Association of serum podocalyxin levels with peripheral arterial disease in patients with type 2 diabetes.J Diabetes Complications. 2019 Jul;33(7):495-499. doi: 10.1016/j.jdiacomp.2019.04.003. Epub 2019 Apr 14.
• [18] First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis.Clin Sci (Lond). 2019 Jan 3;133(1):9-21. doi: 10.1042/CS20180676. Print 2019 Jan 15.
• [19] Genetic analysis of PODXL gene in patients with familial and young-onset Parkinson's disease in a Taiwanese population.Neurobiol Aging. 2019 Dec;84:235.e9-235.e10. doi: 10.1016/j.neurobiolaging.2019.08.027. Epub 2019 Sep 8.
• [20] Overexpression of the Pluripotent Stem Cell Marker Podocalyxin in Prostate Cancer.Anticancer Res. 2018 Nov;38(11):6361-6366. doi: 10.21873/anticanres.12994.
• [21] Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism. J Med Genet. 2016 Jul;53(7):450-6. doi: 10.1136/jmedgenet-2015-103459. Epub 2016 Feb 10.
• [22] The first identified heterozygous nonsense mutations in podocalyxin offer new perspectives on the biology of podocytopathies.Clin Sci (Lond). 2019 Feb 8;133(3):443-447. doi: 10.1042/CS20181067. Print 2019 Feb 14.
• [23] miR-509-3-5P inhibits the invasion and lymphatic metastasis by targeting PODXL and serves as a novel prognostic indicator for gastric cancer.Oncotarget. 2017 May 23;8(21):34867-34883. doi: 10.18632/oncotarget.16802.
• [24] Podocalyxin Is a Marker of Poor Prognosis in Pancreatic Ductal Adenocarcinoma.PLoS One. 2015 Jun 8;10(6):e0129012. doi: 10.1371/journal.pone.0129012. eCollection 2015.
• [25] NNT-AS1 enhances bladder cancer cell growth by targeting miR-1301-3p/PODXL axis and activating Wnt pathway.Neurourol Urodyn. 2020 Feb;39(2):547-557. doi: 10.1002/nau.24238. Epub 2019 Nov 29.
• [26] Podocalyxin influences malignant potential by controlling epithelial-mesenchymal transition in lung adenocarcinoma.Cancer Sci. 2017 Mar;108(3):528-535. doi: 10.1111/cas.13142.
• [27] The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis.Lupus. 2018 Mar;27(3):484-493. doi: 10.1177/0961203317734918. Epub 2017 Oct 19.
• [28] 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.
• [29] 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.
• [30] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [31] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [32] 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.
• [33] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [34] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [35] 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.
• [36] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [37] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [38] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [39] 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.
• [40] 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.
• [41] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [42] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [43] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [44] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [45] 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.
• [46] 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.
• [47] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [48] 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.