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- 저자 : Languino, Lucia R. (검색결과 1 건)
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MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer
Seo, Jae Ho,Chae, Young Chan,Kossenkov, Andrew V.,Lee, Yu Geon,Tang, Hsin-Yao,Agarwal, Ekta,Gabrilovich, Dmitry I.,Languino, Lucia R.,Speicher, David W.,Shastrula, Prashanth K.,Storaci, Alessandra Mar American Association for Cancer Research 2019 Cancer Research Vol.79 No.24
<P>These findings describe mitochondrial fission regulation using a peptidomimetic agent that disturbs the MFF-VDAC complex and displays anticancer activity in multiple tumor models.</P><P><B></B></P><P>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 <SMALL>D</SMALL>-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.</P><P><B>Significance:</B></P><P>These findings describe mitochondrial fission regulation using a peptidomimetic agent that disturbs the MFF–VDAC complex and displays anticancer activity in multiple tumor models.</P><P><I>See related commentary by Rao, p. 6074</I></P>
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