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 Maria; Ferrero, Stefano; Gaudioso, Gabriella; Caroli, Manuela; Tosi, Davide; Giroda, Massimo; Vaira, Valentina; Rebecca, Vito W.; Herlyn, Meenhard; Xiao, Min; Fingerman, Dylan; Martorella, Alessandra; Skordalakes, Emmanuel; Altieri, Dario C.

doi:10.1158/0008-5472.can-19-1982

Cited by 45 publications

(29 citation statements)

References 51 publications

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“…These data are in accordance with previous studies showing that MFF-dependent mitochondrial fission activates signaling pathways involved in the inhibition of cell viability and the activation of the apoptotic response (44). In particular, MFF and other mediators involved in mitochondrial fragmentation such as DRP1 play an integral role in cancer cell death in response to diverse stimuli, including several anticancer drugs (45,46). At least some of these effects could be attributed to the generation of mitochondrial ROS, which would thereafter trigger apoptotic cell death (47).…”

Section: Discussionsupporting

confidence: 93%

“…Therefore, the pharmacological manipulation of mitochondrial fission may serve as an actionable tool to eradicate cancer cells, with tumor initiating capabilities. Accordingly, it has been recently shown that an MFF peptidomimetic strategy elicits anti-cancer activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids, as well as glioblastoma neurospheres (45).…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity

et al. 2020

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Elevated mitochondrial biogenesis and metabolism represent key features of breast cancer stem cells (CSCs), whose propagation is conducive to disease onset and progression. Therefore, interfering with mitochondria biology and function may be regarded as a useful approach to eradicate CSCs. Here, we used the breast cancer cell line MCF7 as a model system to interrogate how mitochondrial fission contributes to the development of mitochondrial dysfunction toward the inhibition of metabolic flux and stemness. We generated an isogenic MCF7 cell line transduced with Mitochondrial Fission Factor (MCF7-MFF), which is primarily involved in mitochondrial fission. We evaluated the biochemical, molecular and functional properties of MCF7-MFF cells, as compared to control MCF7 cells transduced with the empty vector (MCF7-Control). We observed that MFF over-expression reduces both mitochondrial mass and activity, as evaluated using the mitochondrial probes MitroTracker Red and MitoTracker Orange, respectively. The analysis of metabolic flux using the Seahorse XFe96 revealed the inhibition of OXPHOS and glycolysis in MCF7-MFF cells, suggesting that increased mitochondrial fission may impair the biochemical properties of these organelles. Notably, CSCs activity, assessed by 3D-tumorsphere assays, was reduced in MCF7-MFF cells. A similar trend was observed for the activity of ALDH, a well-established marker of stemness. We conclude that enhanced mitochondrial fission may compromise CSCs propagation, through the impairment of mitochondrial function, possibly leading to a quiescent cell phenotype. Unbiased proteomic analysis revealed that proteins involved in mitochondrial dysfunction, oxidative stress-response, fatty acid metabolism and hypoxia signaling are among the most highly up-regulated in MCF7-MFF cells. Of note, integrated analysis of top regulatory networks obtained from unbiased proteomics in MCF7-MFF cells predicts that this cell phenotype activates signaling systems and effectors involved in the inhibition of cell survival and adhesion, together with the activation of specific breast cancer cell death programs. Overall, our study shows that unbalanced and abnormal Sánchez-Alvarez et al. MFF Reduces CSCs Activity activation of mitochondrial fission may drive the impairment of mitochondrial metabolic function, leading to inhibition of CSC propagation, and the activation of quiescence programs. Exploiting the potential of mitochondria to control pivotal events in tumor biology may, therefore, represent a useful tool to prevent disease progression.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity

et al. 2020

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“…If this can be generalized to most PCa cases, it would suggest that targeting the TLK1> Nek1> VDAC1 axis could greatly improve the response to appropriate DNA damaging agents. Interestingly, while this paper was undergoing review, an important paper was published, which showed the Mitochondrial Fission Factors (MFF1 and MFF2) formed homo-and heterodimeric complexes with VDAC1 [25]. A cell permeable MFF Ser223-Leu243 D-enantiomeric peptidomimetic disrupted the MFF-VDAC1 complex and acutely depolarized mitochondria triggering apoptosis in several tumors types and in xerografts, but had no effect on normal cells.…”

Section: Discussionmentioning

confidence: 99%

“…A cell permeable MFF Ser223-Leu243 D-enantiomeric peptidomimetic disrupted the MFF-VDAC1 complex and acutely depolarized mitochondria triggering apoptosis in several tumors types and in xerografts, but had no effect on normal cells. Among the cell lines they investigated, they included several PCa lines: LNCaP, C4-2, C4-2B, PC3, and DU145 [25]. Therefore, there is already some indirect evidence that targeting VDAC1 activity, through its phosphorylation by activated Nek1, via inhibition of TLK1 activity could be a very useful means to enhancing PCa cells killing with focused XRT or doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

The TLK1/Nek1 axis contributes to mitochondrial integrity and apoptosis prevention via phosphorylation of VDAC1

2020

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“…Mff, a key molecule that determines mitochondrial size and shape and the regulation of mitochondrial cell death, is a novel therapeutic target in cancer. 29,30 LATS2 facilitates the apoptosis of non-small cell lung cancer by regulating Mff-induced mitochondrial fission. 31 Furthermore, Mff-induced mitochondrial fission was attributed to decreased colorectal cancer cell viability.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation

Wu¹,

Mao²,

Chen³

et al. 2020

Preprint

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Chemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. Our findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients

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MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer

Cited by 45 publications

References 51 publications

Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity

Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity

The TLK1/Nek1 axis contributes to mitochondrial integrity and apoptosis prevention via phosphorylation of VDAC1

Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation

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