A MYC–GCN2–eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer

Schmidt, Stefanie; Uthe, Friedrich W.; Denk, Sarah; Paauwe, Madelon; Matthes, Niels; Diefenbacher, Markus E.; Bryson, Sheila; Warrander, Fiona; Erhard, Florian; Ade, Carsten P.; Baluapuri, Apoorva; Walz, Susanne; Jackstadt, René; Ford, Catriona A.; Vlachogiannis, Georgios; Valeri, Nicola; Otto, Christoph; Schülein-Völk, Christina; Maurus, Katja; Schmitz, W.; Knight, John R. P.; Wolf, Elmar; Strathdee, Douglas; Schulze, Almut; Germer, Christoph‐Thomas; Rosenwald, Andreas; Sansom, Owen J.; Eilers, Martin; Wiegering, Armin

doi:10.1038/s41556-019-0408-0

Cited by 68 publications

(84 citation statements)

References 72 publications

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“…Accordingly, overexpression of ribosomal proteins (RPs) and enhanced ribosome biogenesis in general has been established as an early event during CRC tumorigenesis [42]. APC deficiency, via MYC upregulation, regulates many more genes associated with translation and is also implicated in balancing the cellular responses to stress signaling by influencing activities of stress-related kinases and the eIF2α/eIF2B complex [12]. It is likely that this latter mechanism is necessary for fine-tuning the rates of protein synthesis and the stress response in CRC cells throughout all adenoma-carcinoma stages to ensure tumor cell survival.…”

Section: The Adenoma-carcinoma Sequence and Its Impact On Deregulatiomentioning

confidence: 99%

“…CRC cells lacking functional APC activate upstream binding factor (UBF), a factor necessary for rDNA transcription, thereby enhancing the expression of pre-45S rRNA in human CRC tissue samples and cell lines, which correlates with poor survival [66]. Furthermore, recent studies validated that APC deficiency in CRC upregulates the expression of genes encoding RPs and auxiliary factors of ribosome assembly, and enhances protein synthesis rates [11,12,66].…”

Section: Deregulation Of Ribosome Biogenesis In Crcmentioning

confidence: 99%

“…Dysregulation of these mechanisms is frequently observed in a variety of tumor entities, including CRC, and many links between oncogenic alterations and the translation machinery have been established [8][9][10]. Accordingly, the rates of protein synthesis are generally enhanced in malignant intestinal tissues as compared to normal tissues, making protein synthesis an attractive target for anti-CRC therapy [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…protein synthesis are generally enhanced in malignant intestinal tissues as compared to normal tissues, making protein synthesis an attractive target for anti-CRC therapy [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Protein Synthesis in Colorectal Cancer

Schmidt

Denk

Wiegering

2020

Cancers

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Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy.

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Section: The Adenoma-carcinoma Sequence and Its Impact On Deregulatiomentioning

confidence: 99%

Section: Deregulation Of Ribosome Biogenesis In Crcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…protein synthesis are generally enhanced in malignant intestinal tissues as compared to normal tissues, making protein synthesis an attractive target for anti-CRC therapy [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Protein Synthesis in Colorectal Cancer

Schmidt

Denk

Wiegering

2020

Cancers

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“…Similar to the situation for genetic lesions, the restriction of the hyperactivation to cancer cells provides an exploitable therapeutic opportunity. Accordingly, several unbiased genetic screens have validated the concept of synthetic lethality associated with the MYC protein family, 57,[63][64][65][66][67][68][69][70] and these screens have been supported by many observations that postulate a synthetic lethal relationship of MYC with the splicing machinery and the arginine methyltransferase PRMT5, 71 CHK1, 72 cyclin-dependent kinase 1/2, [73][74][75] Aurora kinases, [76][77][78] death-receptor engagement, 79 PIM1, 80,81 BET inhibition, 82,83 polo-like kinase 1, 84 the mitotic machinery, 85,86 and protein homoeostasis. 87,88 These data suggest that MYC drives the cellular machineries that are responsible for splicing, protein homoeostasis, transcription, replication, or mitosis, to a limit beyond which cells cannot cope with any additional stress targeting these particular processes.…”

Section: Myc and Synthetic Dosage Lethal Interactionmentioning

confidence: 99%

The SUMO pathway in pancreatic cancer: insights and inhibition

et al. 2020

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An urgent medical need to develop novel treatment strategies for patients with pancreatic ductal adenocarcinoma (PDAC) exists. However, despite various efforts in the histopathological and molecular subtyping of PDAC, novel targeted or specific therapies have not been established. Posttranslational modifications (PTMs) with ubiquitin-like proteins, including small ubiquitin-like modifiers (SUMOs), mediate numerous processes that can contribute to the fitness and survival of cancer cells. The contribution of SUMOylation to transcriptional control, DNA repair pathways, mitotic progression, and oncogenic signalling has been described. Here we review functions of the SUMO pathway in PDAC, with a special focus on its connection to an aggressive subtype of the disease characterised by high MYC activity, and discuss SUMOylation inhibitors under development for precise PDAC therapies.

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RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells

et al. 2022

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Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461‐induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC‐interacting zinc‐finger protein 1 (MIZ1)‐ and retinoblastoma protein (Rb)‐dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine‐ and patient‐derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

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A MYC–GCN2–eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer

Cited by 68 publications

References 72 publications

Targeting Protein Synthesis in Colorectal Cancer

Targeting Protein Synthesis in Colorectal Cancer

The SUMO pathway in pancreatic cancer: insights and inhibition

RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells

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