Abstract：
: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.See related commentary by Rao, p. 6074.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Seo JH,Chae YC,Kossenkov AV,Lee YG,Tang HY,Agarwal E,Gabrilovich DI,Languino LR,Speicher DW,Shastrula PK,Storaci AM,Ferrero S,Gaudioso G,Caroli M,Tosi D,Giroda M,Vaira V,Rebecca VW,Herlyn M,Xiao M,Fingerman D,Madoi
10.1158/0008-5472.CAN-19-1982subject
Has Abstractpub_date
2019-12-15 00:00:00pages
6215-6226issue
24eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-1982journal_volume
79pub_type
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