eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer

Muller, David C.; Shin, Sauyeun; Rugy, Théo Goullet de; Samain, Rémi; Baer, Romain; Strehaïano, Manon; Masvidal-Sanz, Laia; Guillermet-Guibert, Julie; Jean, Christine; Tsukumo, Yoshinori; Sonenberg, Nahum; Marion, Frédéric; Guilbaud, Nicolas; Hoffmann, Jean-Sébastien; Larsson, Ola; Bousquet, Corinne; Pyronnet, Stéphane; Martineau, Yvan

doi:10.1172/jci.insight.121951

Cited by 28 publications

(30 citation statements)

References 43 publications

(79 reference statements)

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“…Currently, the treatment methods for pancreatic cancer mainly include chemotherapy, radiotherapy, surgical treatment, and targeted treatment, but most have little effect (21)(22)(23)(24)(25). Although current pancreatic cancer therapeutic targets have achieved certain therapeutic effects, novel effective therapeutic targets are urgently needed and thereby, a deeper understanding of the pathogenesis of pancreatic cancer is required (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target

Gao¹,

Ren²,

Yu³

et al. 2020

Ann Transl Med

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Background: In recent research, high expression of kinesin family member 23 (KIF23), one of the kinesin motor proteins involved in the regulation of cytokinesis, has been shown to be related to poor prognosis in glioma and paclitaxel-resistant gastric cancer, as a results of the enhancement of proliferation, migration, and invasion. In this study, we analyzed the role of KIF23 in the progression of pancreatic ductal adenocarcinoma.Methods: A bioinformatic method was used to analyze the KIF23 mRNA level in pancreatic tumor tissues compared with normal pancreatic tissues and to analyze the connection between high KIF23 expression and prognosis. We examined the expression of KIF23 using immunohistochemistry and analyzed the connection between the expression of KIF23 and clinicopathological features in pancreatic ductal adenocarcinoma patients. In addition, a colony formation assay, MTT assay, and western blot assay were performed in vitro, along with a mouse xenograft model in vivo, to analyze the effect of KIF23 on proliferation. Further, the correlation between KIF23 and CDCA8 was analyzed by TCGA and immunohistochemical data.Results: Bioinformatic results showed that KIF23 mRNA expression was higher in pancreatic tumor tissues than in normal pancreatic tissues and a poor prognosis has been linked to the high expression of KIF23.Immunohistochemistry revealed that KIF23 was highly expressed at the protein level and high expression of KIF23 correlated with adverse clinicopathological features. Our experimental results demonstrated that knockdown of KIF23 could inhibit the proliferation of pancreatic cells. Further, a positive correlation between KIF23 and CDCA8 expression existed, and KIF23 might promote pancreatic cancer proliferation by affecting CDCA8 expression.Conclusions: Our data showed that high expression of KIF23 is associated with a poor prognosis, and KIF23 might be a potential therapeutic target for pancreatic ductal adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target

Gao¹,

Ren²,

Yu³

et al. 2020

Ann Transl Med

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“…For example, silvestrol significantly inhibited the growth of MDA-MB-231 orthotopic xenograft tumors [20]. Inhibition of eIF4A is also a promising strategy for other cancer types including pancreatic cancer [21]. New amidino-rocaglate derivatives have recently been developed with an IC 50 value as low as 0.97 nM in MDA-MB-231 cells [22,23].…”

Section: Introductionmentioning

confidence: 99%

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

Howard

Estrada

Terrero

et al. 2020

Cancers

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The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5’-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients.

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“…Moreover, aberrant expression of CDT1, CDC6, and ORC or abrogation of their regulation results in re-replication of the genome, leading to genome instability (51)(52)(53). mTOR signaling has been shown to promote DNA replication origin licensing through upregulating CDC6 (54,55). CDC6 is essential for the loading of the MCM2-7 complex during DNA replication.…”

Section: Akt-mtor Signaling In Cell Cycle Progression and Dna Replicationmentioning

confidence: 99%

Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy

Shen

Chen

et al. 2021

Ann Transl Med

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Objective: To summarize the roles of AKT-mTOR signaling in the regulation of the DNA damage response and PD-L1 expression in cancer cells, and propose a novel strategy of targeting AKT-mTOR signaling in combination with radioimmunotherapy in the era of cancer immunotherapy Background: Immunotherapy has greatly improved the clinical outcomes of many cancer patients and has changed the landscape of cancer patient management. However, only a small subgroup of cancer patients (~20-30%) benefit from immune checkpoint blockade-based immunotherapy. The current challenge is to find biomarkers to predict the response of patients to immunotherapy and strategies to sensitize patients to immunotherapy.Methods: Search and review the literature which were published in PUBMED from 2000-2021 with the key words mTOR, AKT, drug resistance, DNA damage response, immunotherapy, PD-L1, DNA repair, radioimmunotherapy.Conclusions: More than 50% of cancer patients receive radiotherapy during their course of treatment.Radiotherapy has been shown to reduce the growth of locally irradiated tumors as well as metastatic nonirradiated tumors (abscopal effects) by affecting systemic immunity. Consistently, immunotherapy has been demonstrated to enhance radiotherapy with more than one hundred clinical trials of radiation in combination with immunotherapy (radioimmunotherapy) across cancer types. Nevertheless, current available data have shown limited efficacy of trials testing radioimmunotherapy. AKT-mTOR signaling is a major tumor growth-promoting pathway and is upregulated in most cancers. AKT-mTOR signaling is activated by growth factors as well as genotoxic stresses including radiotherapy. Importantly, recent advances have shown that AKT-mTOR is one of the main signaling pathways that regulate DNA damage repair as well as PD-L1 levels in cancers. These recent advances clearly suggest a novel cancer therapy strategy by targeting AKT-mTOR signaling in combination with radioimmunotherapy.

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eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer

Cited by 28 publications

References 43 publications

KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target

KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy

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