Mitohormesis Primes Tumor Invasion and Metastasis

Kenny, Timothy; Craig, Amanda; Villanueva, Augusto; Germain, Doris

doi:10.1016/j.celrep.2019.04.095

Cited by 75 publications

(76 citation statements)

References 98 publications

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“…Concurrent with our findings, SIRT3 has been implicated in anoikis resistance of oral squamous cell carcinoma cells [34], and for the maintenance of mitochondrial ROS scavenging in GBM stem cells [24]. In addition, the SIRT3/FOXO3a/SOD2 axis is upregulated as part of the mtUPR and necessary for breast cancer metastasis [25, 35]. Moreover, we and others have demonstrated that SOD2 is required by metastatic cells as an adaptation to oxidative stress, for the maintenance of mitochondrial fidelity, and as a regulator of mitochondria redox signaling [20, 36–38].…”

Section: Discussionsupporting

confidence: 73%

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Kim

Gupta-Vallur

Jones

et al. 2019

Preprint

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Cells must alter their antioxidant capacity for maximal metastatic potential. However, the antioxidant adaptations required for transcoelomic metastasis, which is the passive dissemination of cancer cells in the peritoneal cavity as seen in ovarian cancer, have largely remained unexplored. Contradicting the need for oxidant scavenging by tumor cells is the observation that expression of the nutrient stress sensor and regulator of mitochondrial antioxidant defenses, SIRT3, is suppressed in many primary tumors. We discovered that this mitochondrial deacetylase is however, upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase SOD2. This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent transcriptional increases in SOD2 during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 up-regulation and SIRT3-mediated oxidant scavenging following matrix detachment are required for anoikis resistance in vitro, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.

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Section: Discussionsupporting

confidence: 73%

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Kim

Gupta-Vallur

Jones

et al. 2019

Preprint

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“…This response shares similarities with the UPR mt , a homeostatic stress signaling response induced upon accumulation of misfolded proteins in the mitochondrial matrix (Shpilka and Haynes, 2017). Interestingly, is has been shown that the UPR mt is induced as an adaptive response in cells experiencing the Warburg effect (Kenny et al, 2019), suggesting that the previously reported effector-induced shift in mitochondrial metabolism (Escoll et al, 2017) might cause the induction of a UPR mt -like stress response in infected cells. However, it is also possible that the translocation of bacterial effectors into host cell mitochondria (Degtyar et al, 2009;Dolezal et al, 2012) might activate this stress response.…”

Section: Lp Induces a Mitochondrial Stress Responsementioning

confidence: 60%

Dynamic proteomics profiling ofLegionella pneumophilainfection unveils modulation of the host mitochondrial stress response pathway

Noack

Jimenez-Morales

Stevenson

et al. 2020

Preprint

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The human pathogen Legionella pneumophila (L.p.) secretes ~330 bacterial effector proteins into the host cell which interfere with numerous cellular pathways and often regulate host cell proteins through post-translational modifications. However, the cellular targets and functions of most L.p. effectors are not known. In order to obtain a global overview of potential targets of these effectors, we analyzed the host cell proteome, ubiquitinome, and phosphoproteome during L.p. infection. Our analysis reveals dramatic spatiotemporal changes in the host cell proteome that are dependent on the secretion of bacterial effectors. Strikingly, we show that L.p. substantially reshapes the mitochondrial proteome and modulates mitochondrial stress response pathways such as the mitochondrial unfolded protein response (UPR mt ). To our knowledge, this is the first evidence of manipulation of the UPR mt by a bacterial pathogen in mammalian cells. In addition, we have identified a previously uncharacterized L.p. effector that is targeted to host cell mitochondria and protects mitochondrial network integrity during mitochondrial stress.

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“…Interestingly, the SIRT3 axis of UPR mt was shown to induce the antioxidant proteins superoxide dismutase 2 (SOD2) and catalase, and the subsequent elimination of irreversibly damaged mitochondria through mitophagy [ 47 ]. The SIRT3 arm molecular signature of the UPR mt was recently shown to contribute to breast cancer invasiveness and may be an essential mechanism for cancer cells to adapt to proteotoxic and mitochondrial stress, a process called mitohormesis [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-11 Promotes Early Mouse Mammary Gland Tumor Growth through Metabolic Reprogramming and Increased IGF1/AKT/FoxO1 Signaling Pathway, Enhanced ER Stress and Alteration in Mitochondrial UPR

Tan

Jaulin

Bund

et al. 2020

Cancers

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Matrix metalloproteinase 11 (MMP11) is an extracellular proteolytic enzyme belonging to the matrix metalloproteinase (MMP11) family. These proteases are involved in extracellular matrix (ECM) remodeling and activation of latent factors. MMP11 is a negative regulator of adipose tissue development and controls energy metabolism in vivo. In cancer, MMP11 expression is associated with poorer survival, and preclinical studies in mice showed that MMP11 accelerates tumor growth. How the metabolic role of MMP11 contributes to cancer development is poorly understood. To address this issue, we developed a series of preclinical mouse mammary gland tumor models by genetic engineering. Tumor growth was studied in mice either deficient (Loss of Function-LOF) or overexpressing MMP11 (Gain of Function-GOF) crossed with a transgenic model of breast cancer induced by the polyoma middle T antigen (PyMT) driven by the murine mammary tumor virus promoter (MMTV) (MMTV-PyMT). Both GOF and LOF models support roles for MMP11, favoring early tumor growth by increasing proliferation and reducing apoptosis. Of interest, MMP11 promotes Insulin-like Growth Factor-1 (IGF1)/protein kinase B (AKT)/Forkhead box protein O1 (FoxO1) signaling and is associated with a metabolic switch in the tumor, activation of the endoplasmic reticulum stress response, and an alteration in the mitochondrial unfolded protein response with decreased proteasome activity. In addition, high resonance magic angle spinning (HRMAS) metabolomics analysis of tumors from both models established a metabolic signature that favors tumorigenesis when MMP11 is overexpressed. These data support the idea that MMP11 contributes to an adaptive metabolic response, named metabolic flexibility, promoting cancer growth.

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Mitohormesis Primes Tumor Invasion and Metastasis

Cited by 75 publications

References 98 publications

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Dynamic proteomics profiling ofLegionella pneumophilainfection unveils modulation of the host mitochondrial stress response pathway

Matrix Metalloproteinase-11 Promotes Early Mouse Mammary Gland Tumor Growth through Metabolic Reprogramming and Increased IGF1/AKT/FoxO1 Signaling Pathway, Enhanced ER Stress and Alteration in Mitochondrial UPR

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