Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9OL16U)

• DOT Name: Pleckstrin homology domain-containing family F member 1 (PLEKHF1)
• Synonyms: PH domain-containing family F member 1; Lysosome-associated apoptosis-inducing protein containing PH and FYVE domains; Apoptosis-inducing protein; PH and FYVE domain-containing protein 1; Phafin-1; Zinc finger FYVE domain-containing protein 15
• Gene Name: PLEKHF1
• Related Disease:
  Advanced cancer
  Bladder cancer
  Cognitive impairment
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: PKHF1_HUMAN
• Pfam ID: PF01363 ; PF00169
• Sequence:
  MVDHLANTEINSQRIAAVESCFGASGQPLALPGRVLLGEGVLTKECRKKAKPRIFFLFND
  ILVYGSIVLNKRKYRSQHIIPLEEVTLELLPETLQAKNRWMIKTAKKSFVVSAASATERQ
  EWISHIEECVRRQLRATGRPPSTEHAAPWIPDKATDICMRCTQTRFSALTRRHHCRKCGF
  VVCAECSRQRFLLPRLSPKPVRVCSLCYRELAAQQRQEEAEEQGAGSPGQPAHLARPICG
  ASSGDDDDSDEDKEGSRDGDWPSSVEFYASGVAWSAFHS
• Function: May induce apoptosis through the lysosomal-mitochondrial pathway. Translocates to the lysosome initiating the permeabilization of lysosomal membrane (LMP) and resulting in the release of CTSD and CTSL to the cytoplasm. Triggers the caspase-independent apoptosis by altering mitochondrial membrane permeabilization (MMP) resulting in the release of PDCD8.
• Tissue Specificity: Highly expressed in heart and skeletal muscle. Weakly expressed in brain, thymus, spleen, kidney, liver, small intestine, placenta and lung.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[16]

11 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 Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[14]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[15]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[10]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[17]
4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol	DMTMLXU	Investigative	4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol decreases the expression of Pleckstrin homology domain-containing family F member 1 (PLEKHF1).	[11]

References

• [1] TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells.Oncogene. 2004 Feb 5;23(5):1153-65. doi: 10.1038/sj.onc.1207224.
• [2] Apoptin induces apoptosis in human bladder cancer EJ and BIU-87 cells.Asian Pac J Cancer Prev. 2012;13(1):135-8. doi: 10.7314/apjcp.2012.13.1.135.
• [3] Co-treatment of buspirone with atypical antipsychotic drugs (AAPDs) improved neurocognitive function in chronic schizophrenia.Schizophr Res. 2019 Jul;209:135-140. doi: 10.1016/j.schres.2019.05.006. Epub 2019 May 14.
• [4] Apoptin-modified human mesenchymal stem cells inhibit growth of lung carcinoma in nude mice.Mol Med Rep. 2015 Jul;12(1):1023-9. doi: 10.3892/mmr.2015.3501. Epub 2015 Mar 17.
• [5] URI is an oncogene amplified in ovarian cancer cells and is required for their survival. Cancer Cell. 2011 Mar 8;19(3):317-32. doi: 10.1016/j.ccr.2011.01.019.
• [6] Enhancing apoptosis and overcoming resistance of gemcitabine in pancreatic cancer with bortezomib: a role of death-associated protein kinase-related apoptosis-inducing protein kinase 1.Tumori. 2009 Nov-Dec;95(6):796-803. doi: 10.1177/030089160909500624.
• [7] Use of the probasin promoter ARR2PB to express Bax in androgen receptor-positive prostate cancer cells.J Natl Cancer Inst. 2001 Sep 5;93(17):1314-24. doi: 10.1093/jnci/93.17.1314.
• [8] 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.
• [9] 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.
• [10] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [11] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [12] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [13] 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.
• [14] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [15] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [16] 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.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.