NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism

Chen, Chialin; Kumar, Dinesh Babu Uthaya; Punj, Vasu; Xu, Jun; Sher, Linda; Tahara, Stanley M.; Hess, Sonja; Machida, Keigo

doi:10.1016/j.cmet.2015.12.004

Cited by 304 publications

(294 citation statements)

References 29 publications

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“…In contrast, hypoxia triggers early differentiation in mouse ES cells [76]. Although respiratory rates can be retained during acute hypoxia due to the low K m of mitochondrial cytochrome c oxidase [85,86], hypoxic stabilization of HIF-1a can be observed at 5% O 2 [87].…”

Section: Stem Cell Nichesmentioning

confidence: 95%

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Mitochondrial functions in stem cells

Margineantu

Hockenbery

2016

Current Opinion in Genetics & Development

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Section: Stem Cell Nichesmentioning

confidence: 95%

“…TICs, exhibit mitochondrial FAO as a mechanism for apoptosis resistance [75] and downregulation of ROS [76]. Thus, similar to hematopoietic stem cells, the combination of mitochondrial FAO and aerobic glycolysis may have advantages for preservation of 'stemness'.…”

Section: Leukemia-initiating Cells and Hepatocellular Carcinomamentioning

confidence: 98%

Mitochondrial functions in stem cells

Margineantu

Hockenbery

2016

Current Opinion in Genetics & Development

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“…Changes in mitochondrial dynamics and energy homeostasis are emerging as important elements in cancer (18,19). These processes might be particularly relevant for tumor-initiating cancer stem-like cells, which exhibit greater metabolic plasticity (40,41) and often increased reliance on mitochondrial functions (42)(43)(44). We show that the drug's lethal effects were directly related to the interference with mSTAT3 and mitochondrial function using isolated mitochondria from STAT3 −/− MEF and mitochondria-depleted cancer cells, which were insensitive to OPB-51602.…”

Section: Proteotoxic Stat3 Aggregate Formation and In Vivo Antitumormentioning

confidence: 99%

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

Genini

Brambilla

Laurini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using highaffinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies.S ignal transducer and activator of transcription 3 (STAT3) is a key element in multiple signaling pathways and is aberrantly activated in many human cancers (1, 2). STAT3 promotes cell proliferation, survival, angiogenesis, and immune-evasion (1-3). Phosphorylation at Tyr705 (pTyr705), catalyzed by Janus kinases (JAK) and other tyrosine kinases, induces STAT3 dimerization through the interaction of the SH2 domain (SH2D), nuclear accumulation, and target gene transcription (1, 3, 4). Emerging evidence indicates that STAT3 also localizes to mitochondria and controls mitochondrial functions (2, 5-7). Mitochondrial localized STAT3 (mSTAT3) is critical for survival of RAStransformed mouse embryo fibroblasts (MEF) under glucosestarvation, reflecting a specific dependency of cancer cells on mitochondria in certain conditions (6). Interestingly, mSTAT3 is prevalently phosphorylated at Ser727 (pSer727), which enhances its mitochondrial functions (5, 6). Furthermore, constitutive pSer727 is found in many human cancers and is apparently sufficient to drive tumorigenesis in various model systems (8-10).STAT3 is an attractive cancer therapeutic target because of its central role in multiple oncogenic processes and great effort has been devoted in recent years to discover STAT3 inhibitors (STAT3i) (11,12). To date, small-molecule STAT3i have shown relevant activity in preclinical models and few of them are currently investigated in clinical trials (11,(13)(14)(15)(16)(17). However, an important gap persists in our knowledge of the biological mechanisms of antitumor activity, the critical cellular processes affected, and the factors determining sensitivity of cancer cells to STAT3i, hindering further clinical development of these highly promising anticancer drugs. Indeed, great atten...

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“…Embryonic stem cells share several metabolic features with cancer to maintain their rapid cell cycles and epigenetic landscape necessary for multilineage potency (13)(14)(15). As with stem cells, tumor cells require concerted dysregulation of metabolism and epigenetic cell states to simultaneously accommodate the bioenergetic demands of increased proliferation and aberrant tumor cell fate through epigenetic modification.…”

Section: Introductionmentioning

confidence: 99%