MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer.
Animals
Apoptosis
/ drug effects
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line, Tumor
Humans
Lung Neoplasms
/ drug therapy
Male
Membrane Proteins
/ antagonists & inhibitors
Mice
Mitochondria
/ drug effects
Mitochondrial Dynamics
/ drug effects
Mitochondrial Membranes
/ drug effects
Mitochondrial Proteins
/ antagonists & inhibitors
Permeability
/ drug effects
Protein Multimerization
/ drug effects
Voltage-Dependent Anion Channel 1
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 Dec 2019
15 Dec 2019
Historique:
received:
26
06
2019
revised:
09
09
2019
accepted:
25
09
2019
pubmed:
5
10
2019
medline:
28
5
2020
entrez:
5
10
2019
Statut:
ppublish
Résumé
The regulators of mitochondrial cell death in cancer have remained elusive, hampering the development of new therapies. Here, we showed that protein isoforms of mitochondrial fission factor (MFF1 and MFF2), a molecule that controls mitochondrial size and shape, that is, mitochondrial dynamics, were overexpressed in patients with non-small cell lung cancer and formed homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability. MFF inserted into the interior hole of the VDAC1 ring using Arg225, Arg236, and Gln241 as key contact sites. A cell-permeable MFF Ser223-Leu243 d-enantiomeric peptidomimetic disrupted the MFF-VDAC1 complex, acutely depolarized mitochondria, and triggered cell death in heterogeneous tumor types, including drug-resistant melanoma, but had no effect on normal cells. In preclinical models, treatment with the MFF peptidomimetic was well-tolerated and demonstrated anticancer activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids, and glioblastoma neurospheres. These data identify the MFF-VDAC1 complex as a novel regulator of mitochondrial cell death and an actionable therapeutic target in cancer. SIGNIFICANCE: These findings describe mitochondrial fission regulation using a peptidomimetic agent that disturbs the MFF-VDAC complex and displays anticancer activity in multiple tumor models.
Identifiants
pubmed: 31582380
pii: 0008-5472.CAN-19-1982
doi: 10.1158/0008-5472.CAN-19-1982
pmc: PMC6911621
mid: NIHMS1540747
doi:
Substances chimiques
Membrane Proteins
0
Mff protein, human
0
Mitochondrial Proteins
0
VDAC1 protein, human
0
Voltage-Dependent Anion Channel 1
EC 1.6.-
Types de publication
Journal Article
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
6215-6226Subventions
Organisme : NCI NIH HHS
ID : P01 CA140043
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA224769
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220446
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221838
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2019 American Association for Cancer Research.
Références
Oncotarget. 2015 Jul 10;6(19):17514-31
pubmed: 26020805
Nat Rev Drug Discov. 2016 May;15(5):348-66
pubmed: 26775689
Science. 2011 Nov 25;334(6059):1129-33
pubmed: 22033517
Immunity. 2011 Oct 28;35(4):493-5
pubmed: 22035842
Biochim Biophys Acta. 2012 Jun;1818(6):1457-65
pubmed: 22240010
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
J Biol Chem. 2002 Mar 1;277(9):7610-8
pubmed: 11751859
Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22546-51
pubmed: 21148773
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10396-7
pubmed: 25002521
Nat Cell Biol. 2018 Jul;20(7):755-765
pubmed: 29950571
Trends Cell Biol. 2016 Sep;26(9):655-667
pubmed: 27161573
Am J Physiol. 1999 Jan;276(1):G1-6
pubmed: 9886971
Cell Metab. 2015 Aug 4;22(2):204-6
pubmed: 26073494
Cell Metab. 2017 Jul 5;26(1):39-48
pubmed: 28648983
Nature. 2005 Mar 31;434(7033):658-62
pubmed: 15800627
Nat Commun. 2013;4:2139
pubmed: 23842546
Oncogene. 2013 Oct;32(40):4814-24
pubmed: 23128392
Nat Rev Cancer. 2014 Nov;14(11):709-21
pubmed: 25342630
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Cancer Res. 2016 Oct 15;76(20):5914-5920
pubmed: 27694602
Mol Cell. 2015 Oct 1;60(1):47-62
pubmed: 26387735
Nature. 2017 Oct 5;550(7674):133-136
pubmed: 28953887
Nucleic Acids Res. 2015 Jul 1;43(W1):W419-24
pubmed: 25943545
J Clin Invest. 2016 May 2;126(5):1834-56
pubmed: 27043285
J Cell Biol. 2010 Dec 13;191(6):1141-58
pubmed: 21149567
Breast Cancer Res. 2014 May 30;16(3):R55
pubmed: 24886669
EBioMedicine. 2019 Oct;48:353-363
pubmed: 31542392
Chem Biol. 2015 Feb 19;22(2):196-205
pubmed: 25699603
Genes Dev. 2008 Jun 15;22(12):1577-90
pubmed: 18559474
Nat Rev Mol Cell Biol. 2015 Jun;16(6):329-44
pubmed: 25991373
Mol Cell. 2015 Feb 5;57(3):537-51
pubmed: 25658205
Cell Metab. 2019 Aug 6;30(2):303-318.e6
pubmed: 31130467
Nucleic Acids Res. 2016 Jan 4;44(D1):D1251-7
pubmed: 26450961
J Am Heart Assoc. 2017 Mar 13;6(3):null
pubmed: 28288978
Nat Commun. 2016 Dec 19;7:13730
pubmed: 27991488
Biochim Biophys Acta Bioenerg. 2017 Aug;1858(8):665-673
pubmed: 28283400
Mol Cell. 2015 Feb 5;57(3):521-36
pubmed: 25658204
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15370-5
pubmed: 18832158
Nat Cell Biol. 2007 May;9(5):550-5
pubmed: 17417626
Trends Mol Med. 2015 Sep;21(9):560-70
pubmed: 26186888
Nat Commun. 2018 Nov 26;9(1):4976
pubmed: 30478310
Cancer Cell. 2005 May;7(5):457-68
pubmed: 15894266
Cell Death Dis. 2013 Sep 19;4:e809
pubmed: 24052077
Cell Death Differ. 2018 Jan;25(1):27-36
pubmed: 29099483
Cell Death Differ. 2018 Mar;25(3):486-541
pubmed: 29362479
Biochim Biophys Acta. 2015 Dec;1848(12):3188-96
pubmed: 26407725
Biophys J. 2012 Feb 8;102(3):523-31
pubmed: 22325275
Methods. 2016 Jan 15;93:72-83
pubmed: 26165956
Biochim Biophys Acta Rev Cancer. 2018 Aug;1870(1):96-102
pubmed: 29807044