The ROS/SUMO Axis Contributes to the Response of Acute Myeloid Leukemia Cells to Chemotherapeutic Drugs

Bossis, Guillaume; Sarry, Jean-Emmanuel; Kifagi, Chamseddine; Ristić, Marko; Saland, Estelle; Vergez, François; Salem, Tamara; Boutzen, Héléna; Baik, Hayeon; Brockly, Frédérique; Pelegrin, Mireia; Kaoma, Tony; Vallar, Laurent; Récher, Christian; Manenti, Stéphane; Piechaczyk, Marc

doi:10.1016/j.celrep.2014.05.016

Cited by 87 publications

(86 citation statements)

References 31 publications

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“…H 2 O 2 ) and anticancer drugs used for the treatment of acute myeloid leukemia induce the formation of a disulfide bridge between the catalytic Cys residues of the E1 and the E2 enzymes. This leads to the transient inactivation of both enzymes and the subsequent desumoylation of most cellular substrates (94,95). Interestingly, under the same conditions, the overall ubiquitination was not affected (94).…”

Section: E1 Regulationmentioning

confidence: 80%

“…More recently, it was shown that miRNA30a controls Ubc9 levels in human subcutaneous adipocytes, with consequences for their mitochondrial activity (132). Another way to directly regulate the E2 catalytic activity is the previously-discussed transient disulfide bridge formed between the catalytic cysteines of the E1 and the E2 enzymes (94,95). Not surprisingly, PTMs also represent an additional strategy to regulate E2 function.…”

Section: E2 Regulationmentioning

confidence: 99%

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SUMO conjugation – a mechanistic view

Pichler

Fatouros

Lee

et al. 2017

Biomolecular Concepts

218

223

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Abstract:The regulation of protein fate by modification with the small ubiquitin-related modifier (SUMO) plays an essential and crucial role in most cellular pathways. Sumoylation is highly dynamic due to the opposing activities of SUMO conjugation and SUMO deconjugation. SUMO conjugation is performed by the hierarchical action of E1, E2 and E3 enzymes, while its deconjugation involves SUMO-specific proteases. In this review, we summarize and compare the mechanistic principles of how SUMO gets conjugated to its substrate. We focus on the interplay of the E1, E2 and E3 enzymes and discuss how specificity could be achieved given the limited number of conjugating enzymes and the thousands of substrates.

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Section: E1 Regulationmentioning

confidence: 80%

Section: E2 Regulationmentioning

confidence: 99%

SUMO conjugation – a mechanistic view

Pichler

Fatouros

Lee

et al. 2017

Biomolecular Concepts

218

223

View full text Add to dashboard Cite

show abstract

“…ROS exerts a pivotal role in a number of cellular processes associated with tumor progression, including survival, proliferation, invasion, angiogenesis and metastasis [4-6]. Most of the currently available anti-cancerous chemotherapeutic, photodynamic and radiotherapeutic agents are selectively toxic to tumor cells by augmenting oxidative stress, resulting in sustained cell-cycle inhibition, cell death induction, and senescence, in the present, this likely represents one of the best opportunities for cancer therapeutics [7-9]. Several intracellular sources can contribute to the production of ROS, such as cyclooxygenase, cytochrome P450, lipoxygenases, mitochondrial electron transport, xanthine oxidase and NADPH oxidase (NOX) [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Shen

Xie

et al. 2016

Oncotarget

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Cambogin, a bioactive polycyclic polyprenylated acylphoroglucinol (PPAP) derived from the Garcinia genus, possesses proapoptotic effect in medulloblastoma and breast cancer cells. We have previously demonstrated that the proapoptotic effect of cambogin is driven by the production of reactive oxygen species (ROS). Here we have shown that the inhibitory effect of cambogin on cell proliferation is associated with the loss of mitochondrial transmembrane potential (ΔΨm) and mitochondrial fragmentation. Cambogin also promotes the mutual complex formation of the membrane-bound subunit p22phox of NADPH oxidase 1 (NOX1), as well as the phosphorylation of the cytosolic subunit p47phox, subsequently enhancing membrane-bound NOX1 activity, which leads to increases in intracellular and mitochondrial levels of O2.- and H2O2. Pharmacological inhibition of NOX1 using apocynin (pan-NOX inhibitor), ML171 (NOX1 inhibitor) or siRNA against NOX1 prevents the increases in O2.- and H2O2 levels and the anti-proliferative effect of cambogin. Antioxidants, including SOD (superoxide dismutase), CAT (catalase) and EUK-8, are also able to restore cell viability in the presence of cambogin. Besides, cambogin increases the dissociation of thioredoxin-1 (Trx1) from ASK1, switching the inactive form of ASK1 to the active kinase, subsequently leads to the phosphorylation of JNK/SAPK, which is abolished upon ML171 treatment. The proapoptotic effect of cambogin in breast cancer cells is also aggravated upon knocking down Trx1 in MCF-7 cells. Taken in conjunction, these data indicate that the anti-proliferative and pro-apoptotic effect of cambogin is mediated via inducing NOX1-dependent ROS production and the dissociation of ASK1 and Trx1.

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“…Reactive oxygen species (ROS) can inhibit both the SUMO activating and SUMO conjugating enzymes in a different manner, via the formation of reversible disulfide bridges between the catalytic cysteine residues [90]. It has been reported that several chemotherapeutic drugs used to treat acute myeloid leukemias induce the formation of ROS, thereby inhibiting the SUMO pathway and subsequently reducing tumor growth [91]. Additionally, small SUMO-mimicking peptides can act as SUMOylation inhibitors [92].…”

Section: Targeting the Sumo Systemmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

243

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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The ROS/SUMO Axis Contributes to the Response of Acute Myeloid Leukemia Cells to Chemotherapeutic Drugs

Cited by 87 publications

References 31 publications

SUMO conjugation – a mechanistic view

SUMO conjugation – a mechanistic view

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

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