Targeting cell membrane HDM2: A novel therapeutic approach for acute myeloid leukemia.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
22
03
2019
accepted:
09
05
2019
revised:
30
04
2019
pubmed:
25
7
2019
medline:
1
7
2020
entrez:
25
7
2019
Statut:
ppublish
Résumé
The E3 ligase human double minute 2 (HDM2) regulates the activity of the tumor suppressor protein p53. A p53-independent HDM2 expression has been reported on the membrane of cancer cells but not on that of normal cells. Herein, we first showed that membrane HDM2 (mHDM2) is exclusively expressed on human and mouse AML blasts, including leukemia stem cell (LSC)-enriched subpopulations, but not on normal hematopoietic stem cells (HSCs). Higher mHDM2 levels in AML blasts were associated with leukemia-initiating capacity, quiescence, and chemoresistance. We also showed that a synthetic peptide PNC-27 binds to mHDM2 and enhances the interaction of mHDM2 and E-cadherin on the cell membrane; in turn, E-cadherin ubiquitination and degradation lead to membrane damage and cell death of AML blasts by necrobiosis. PNC-27 treatment in vivo resulted in a significant killing of both AML "bulk" blasts and LSCs, as demonstrated respectively in primary and secondary transplant experiments, using both human and murine AML models. Notably, PNC-27 spares normal HSC activity, as demonstrated in primary and secondary BM transplant experiments of wild-type mice. We concluded that mHDM2 represents a novel and unique therapeutic target, and targeting mHDM2 using PNC-27 selectively kills AML cells, including LSCs, with minimal off-target hematopoietic toxicity.
Identifiants
pubmed: 31337857
doi: 10.1038/s41375-019-0522-9
pii: 10.1038/s41375-019-0522-9
pmc: PMC7951797
mid: NIHMS1065567
doi:
Substances chimiques
PNC-27
0
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
75-86Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL141379
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201184
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233338
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA158350
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180861
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA102031
Pays : United States
Références
Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25:1315–21.
doi: 10.1038/nbt1350
Gentles AJ, Plevritis SK, Page P, Alizadeh AA. Association of a leukemic stem cell gene expression signature with clinical outcome in acute myeloid leukemia. JAMA. 2012;304:2706–15.
doi: 10.1001/jama.2010.1862
Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14:275–91.
doi: 10.1016/j.stem.2014.02.006
Alarcon-Vargas D, Ronai Z. p53-Mdm2-the affair that never ends. Carcinogenesis. 2002;23:541–7.
doi: 10.1093/carcin/23.4.541
Watanabe T, Ichikawa A, Saito H, Hotta T. Overexpression of the MDM2 oncogene in leukemia and lymphoma. Leuk Lymphoma. 1996;21:391–7.
doi: 10.3109/10428199609093436
Capoulade C, Bressac-de Paillerets B, Lefrere I, Ronsin M, Feunteun J, Tursz T. et al. Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt’s lymphoma cells. Oncogene. 1998;16:1603–10.
doi: 10.1038/sj.onc.1201702
Bueso-Ramos CE, Manshouri T, Haidar MA, Yang Y, McCown P, Ordonez N, et al. Abnormal expression of MDM-2 in breast carcinomas. Breast Cancer Res Treat. 1996;37:179–88.
doi: 10.1007/BF01806499
Polsky D, Bastian BC, Hazan C, Melzer K, Pack J, Houghton A, et al. HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. Cancer Res. 2001;61:7642–6.
pubmed: 11606406
Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453–9.
doi: 10.1093/nar/26.15.3453
Fakharzadeh SS, Trusko SP, George DL. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 1991;10:1565–9.
doi: 10.1002/j.1460-2075.1991.tb07676.x
Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci USA. 1998;95:15608–12.
doi: 10.1073/pnas.95.26.15608
Sarafraz-Yazdi E, Bowne WB, Adler V, Sookraj KA, Wu V, Shteyler V, et al. Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes. Proc Natl Acad Sci USA. 2010;107:1918–23.
doi: 10.1073/pnas.0909364107
Kanovsky M, Raffo A, Drew L, Rosal R, Do T, Friedman FK, et al. Peptides from the amino terminal mdm-2-binding domain ofp53, designed from conformational analysis, are selectively cytotoxic to transformed cells. Proc Natl Acad Sci USA. 2001;98:12438–43.
doi: 10.1073/pnas.211280698
Bowne WB, Sookraj KA, Vishnevetsky M, Adler V, Sarafraz-Yazdi E, Lou S. The penetratin sequence in the anticancer PNC-28 peptide causes tumor cell necrosis rather than apoptosis of human pancreatic cancer cells. Ann Surg Oncol. 2008;15:3588–3600.
doi: 10.1245/s10434-008-0147-0
Rosal R, Pincus MR, Brandt-Rauf PW, Fine RL, Michl J, Wang H. NMR solution structure of a peptide from the mdm-2 binding domain of the p53 protein that is selectively cytotoxic to cancer cells. Biochemistry. 2004;43:1854–61.
doi: 10.1021/bi035718g
Michl J, Scharf B, Schmidt A, Huynh C, Hannan R, von Gizycki H, et al. PNC-28, a p53-derived peptide that is cytotoxic to cancer cells, blocks pancreatic cancer cell growth in vivo. Int J Cancer. 2006;119:1577–85.
doi: 10.1002/ijc.22029
Davitt K, Babcock BD, Fenelus M, Poon CK, Sarkar A, Trivigno V, et al. The anti-cancer peptide, PNC-27, induces tumor cell necrosis of a poorly differentiated non-solid tissue human leukemia cell line that depends on expression of HDM-2 in the plasma membrane of these cells. Ann Clin Lab Sci. 2014;44:241–8.
pubmed: 25117093
Sookraj KA, Bowne WB, Adler V, Sarafraz-Yazdi E, Michl J, Pincus MR. The anti-cancer peptide, PNC-27, induces tumor cell lysis as the intact peptide. Cancer Chemother Pharm. 2010;66:325–31.
doi: 10.1007/s00280-009-1166-7
Pincus MR. The physiological structure and function of proteins. In: Sperelakis N editors. Principles of Cell Physiology. 3rd ed. New York, NY, USA: Academic press; 2001. pp 19–42.
doi: 10.1016/B978-012656976-6/50094-9
Dathe M, Wieprecht T. Structural features of helical anti-microbial peptides: their potential to modulate activity on model membranes and biological cells. Biochem Biophys Acta. 1999;1462:71–87.
doi: 10.1016/S0005-2736(99)00201-1
Palmer M, Valeva A, Kehoe M, Bhakdi S. Kinetics of streptolysin O self-assembly. Eur J Biochem. 1995;231:388–95.
doi: 10.1111/j.1432-1033.1995.tb20711.x
Pincus MR, Fenelus M, Sarafraz-Yazdi E, Adler V, Bowne W, Michl J. Anti-cancer peptides from ras-p21 and p53 proteins. Curr Pharm Des. 2011;17:2677–98.
doi: 10.2174/138161211797416075
Li L, Osdal T, Ho Y, Chun S, McDonald T, Agarwal P, et al. SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell Stem Cell. 2014;15:431–46.
doi: 10.1016/j.stem.2014.08.001
Bhatia R, McGlave PB, Dewald GW, Blazar BR, Verfaillie CM. Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages. Blood. 1995;85:3636–45.
doi: 10.1182/blood.V85.12.3636.bloodjournal85123636
Zhang B, Nguyen LXT, Li L, Zhao D, Kumar B, Wu H, et al. Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nat Med. 2018;24:450–62.
doi: 10.1038/nm.4499
Zorko NA, Bernot KM, Whitman SP, Siebenaler RF, Ahmed EH, Marcucci GG, et al. Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias. Blood. 2012;120:1130–6.
doi: 10.1182/blood-2012-03-415067
Yang JY, Zong CS, Xia W, Wei Y, Ali-Seyed M, Li Z, et al. MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation. Mol Cell Biol. 2006;26:7269–82.
doi: 10.1128/MCB.00172-06
Taneyhill LA, Schiffmacher AT. Should I stay or should I go? Cadherin function and regulation in the neural crest. Genesis. 2017;55:1–39.
doi: 10.1002/dvg.23028
Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.
doi: 10.1038/nature20598
Darban SA, Badiee A, Jaafari MR. PNC27 anticancer peptide as targeting ligand significantly improved efficacy of Doxil in HDM2-expressiong cells. Nanomedicine. 2017;12:1475–90.
doi: 10.2217/nnm-2017-0069
Al-toub M, Vishnubalaji R, Hamam R, Kassem M, Aldahmash A, Alajez NM. CDH1 and IL1-beta expression dictates FAK and MAPKK-dependent cross-talk between cancer cells and human mesenchymal stem cells. Stem Cell Res Ther. 2015;6:135.
doi: 10.1186/s13287-015-0123-0
Nishioka C, Ikezoe T, Pan B, Xu K, Yokoyama A. MicroRNA-9 plays a role in interleukin-10-mediated expression of E-cadherin in acute myelogenous leukemia cells. Cancer Sci. 2017;108:685–95.
doi: 10.1111/cas.13170
Ewerth D, Schmidts A, Hein M, et al. Suppression of APC/CCdh1 has subtype specific biological effects in acute myeloid leukemia. Oncotarget. 2016;7:48220–30.
doi: 10.18632/oncotarget.10196