TY - JOUR
T1 - MFF regulation of mitochondrial cell death is a therapeutic target in cancer
AU - Seo, Jae Ho
AU - Chae, Young Chan
AU - Kossenkov, Andrew V.
AU - Lee, Yu Geon
AU - Tang, Hsin Yao
AU - Agarwal, Ekta
AU - Gabrilovich, Dmitry I.
AU - Languino, Lucia R.
AU - Speicher, David W.
AU - Shastrula, Prashanth K.
AU - Storaci, Alessandra Maria
AU - Ferrero, Stefano
AU - Gaudioso, Gabriella
AU - Caroli, Manuela
AU - Tosi, Davide
AU - Giroda, Massimo
AU - Vaira, Valentina
AU - Rebecca, Vito W.
AU - Herlyn, Meenhard
AU - Xiao, Min
AU - Fingerman, Dylan
AU - Martorella, Alessandra
AU - Skordalakes, Emmanuel
AU - Altieri, Dario C.
N1 - Funding Information:
We thank James Hayden and Frederick Keeney for assistance with time-lapse videomicroscopy in the Imaging Core Facility as well as the Proteomics and Metabolomics Core Facility for LC-MS/MS analysis. This work was supported by NIH grants P01 CA140043 (to D.C. Altieri, L.R. Languino, and D.W. Speicher), R35 CA220446 (to D.C. Altieri), R50 CA221838 (to H.-Y. Tang), and R50 CA211199 (to A.V. Kossenkov), by Fondazione Cariplo (2014–1148 to V. Vaira), by the Italian Minister of Health- Ricerca Corrente program 2017 (to S. Ferrero), and by the National Research Foundation of Korea funded by the Ministry of Education (2018R1D1A1B07048104 and 2018R1A6A1A03025810) and the Ministry of Science and ICT (2014M3A9D8034459). Y.C. Chae is the recipient of the Research Fund (1.170074.01) of Ulsan National Institute of Science and Technology and the National Research Foundation of Korea (2014M3A9D8034459) funded by the Ministry of Science and ICT. A.M. Storaci is supported by a fellowship from the
Funding Information:
and Metabolomics Core Facility for LC-MS/MS analysis. This work was supported by NIH grants P01 CA140043 (to D.C. Altieri, L.R. Languino, and D.W. Speicher), R35 CA220446 (to D.C. Altieri), R50 CA221838 (to H.-Y. Tang), and R50 CA211199 (to A.V. Kossenkov), by Fondazione Cariplo (2014–1148 to V. Vaira), by the Italian Minister of Health-Ricerca Corrente program 2017 (to S. Ferrero), and by the National Research Foundation of Korea funded by the Ministry of Education (2018R1D1A1B07048104 and 2018R1A6A1A03025810) and the Ministry of Science and ICT (2014M3A9D8034459). Y.C. Chae is the recipient of the Research Fund (1.170074.01) of Ulsan National Institute of Science and Technology and the National Research Foundation of Korea (2014M3A9D8034459) funded by the Ministry of Science and ICT. A.M. Storaci is supported by a fellowship from the
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-1982
DO - 10.1158/0008-5472.CAN-19-1982
M3 - Article
C2 - 31582380
AN - SCOPUS:85076445310
SN - 0008-5472
VL - 79
SP - 6215
EP - 6226
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -