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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>
Sahakian, E.,Powers, J.J.,Chen, J.,Deng, S.L.,Cheng, F.,Distler, A.,Woods, D.M.,Rock-Klotz, J.,Sodre, A.L.,Youn, J.I.,Woan, K.V.,Villagra, A.,Gabrilovich, D.,Sotomayor, E.M.,Pinilla-Ibarz, J. Pergamon Press 2015 Molecular immunology Vol.63 No.2
Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo. MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies.