Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells

Albert, Alexandra E.; Adua, Sally J.; Cai, Wesley L.; Arnal-Estapé, Anna; Cline, Gary W.; Liu, Zongzhi; Zhao, Minghui; Cao, Paul D.; Mariappan, Malaiyalam; Nguyen, Don X.

doi:10.1158/1541-7786.mcr-19-0245

Cited by 15 publications

(17 citation statements)

References 48 publications

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“…Part of these were also significantly upregulated at the mRNA level in our RNA-seq data (i.e. Pck2 and CHOP), while others were not (Gpx1, PUMA, Bim) (supplementalFigure 3F), possibly reflecting activation of the latter at the translational level, as described in other ISR-related contexts(53,54). Two other known effectors of the ISR, Hrk and NOXA (51), were not expressed in FL mycER cells as judged by our RNA-seq data, precluding assessment of their possible roles in IACS-010759-induced cell death.In order to assess the contribution of the ISR to the cytotoxic action of IACS-010759, we used CRISPR-Cas9 engineering to inactivate the gene encoding CHOP, the main mediator of the proapoptotic branch of the ISR(45).…”

supporting

confidence: 58%

Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

Donati

Ravà

Filipuzzi

et al. 2020

Preprint

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Multiple molecular features, such as activation of specific oncogenes (e. g. MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL). Understanding the relationships between these features and their possible exploitation toward disease classification and therapy remains a major priority in the field. Here, we report that MYC activity in DLBCL is closely correlated with – and most likely a driver of – gene signatures related to Oxidative Phosphorylation (OxPhos). On this basis, we hypothesized that enzymes involved in Oxidative Phosphorylation, and in particular electron-transport chain (ETC) complexes, might constitute tractable therapeutic targets in MYC-associated lymphoma. Indeed, our data show that MYC sensitizes B-cells to IACS-010759, a selective inhibitor of ETC complex I. Mechanistically, IACS-010759 activates an ATF4-driven Integrated Stress Response (ISR), engaging the intrinsic apoptosis pathway through the transcription factor CHOP. In line with these findings, IACS-010759 shows synergy with the BCL2 inhibitor venetoclax against double-hit lymphoma (DHL), a high-grade form of DLBCL with concurrent activation of MYC and BCL2. Similarly, in BCL2-negative lymphoma cell lines, inhibition of the BCL2-related protein Mcl-1 potentiates killing by IACS-010759. Altogether, ETC complex I inhibition engages the ISR to lower the apoptotic threshold in MYC-driven lymphomas and, in combination with select BCL2-family inhibitors, provides a novel therapeutic principle against this aggressive DLBCL subset.Statement of significanceThis work points to OxPhos as a key MYC-activated process and a tractable therapeutic target toward personalized treatment of high-grade DLBCL, providing strong context-dependent cooperation with BH3-mimetic compounds.

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supporting

confidence: 58%

Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

Donati

Ravà

Filipuzzi

et al. 2020

Preprint

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“…Further, pharmacological ISR activation is protective in a Huntingtin mouse model 53 . Nevertheless, deregulated activation of the ISR has also been correlated with cancer and diabetes 54,55 . The ISR is activated in neurogenerative disorders, traumatic brain injury, and Down syndrome [56][57][58][59] .…”

Section: Discussionmentioning

confidence: 99%

Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation

et al. 2021

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Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The integrated stress response (ISR) is a conserved stress-signaling pathway that tunes mRNA translation via phosphorylation of the translation initiation factor eIF2. ISR activation and translation initiation are finely balanced by eIF2 kinases and by the eIF2 guanine nucleotide exchange factor eIF2B. However, the role of the ISR during aging remains poorly understood. Using a genomic mutagenesis screen for longevity in Caenorhabditis elegans, we define a role of eIF2 modulation in aging. By inhibiting the ISR, dominant mutations in eIF2B enhance protein homeostasis and increase lifespan. Consistently, full ISR inhibition using phosphorylation-defective eIF2α or pharmacological ISR inhibition prolong lifespan. Lifespan extension through impeding the ISR occurs without a reduction in overall protein synthesis. Instead, we observe changes in the translational efficiency of a subset of mRNAs, of which the putative kinase kin-35 is required for lifespan extension. Evidently, lifespan is limited by the ISR and its inhibition may provide an intervention in aging.

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“…In addition, pathologic changes caused by viruses can induce cancerous changes in cells, such as HCC development in patients with HCV infection [163,164]. Some studies have shown that eIF2α phosphorylation inhibits c-Myc-mediated glycolysis, thereby inhibiting cancer growth and metastasis [165,166]. Therefore, the study of eIF2α has played an important role in revealing viral pathogenesis and new targeted drug development.…”

Section: Resultsmentioning

confidence: 99%

The role of host eIF2α in viral infection

Liu¹,

Wang²,

Cheng³

et al. 2020

Virol J

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Background eIF2α is a regulatory node that controls protein synthesis initiation by its phosphorylation or dephosphorylation. General control nonderepressible-2 (GCN2), protein kinase R-like endoplasmic reticulum kinase (PERK), double-stranded RNA (dsRNA)-dependent protein kinase (PKR) and heme-regulated inhibitor (HRI) are four kinases that regulate eIF2α phosphorylation. Main body In the viral infection process, dsRNA or viral proteins produced by viral proliferation activate different eIF2α kinases, resulting in eIF2α phosphorylation, which hinders ternary tRNAMet-GTP-eIF2 complex formation and inhibits host or viral protein synthesis. The stalled messenger ribonucleoprotein (mRNP) complex aggregates under viral infection stress to form stress granules (SGs), which encapsulate viral RNA and transcription- and translation-related proteins, thereby limiting virus proliferation. However, many viruses have evolved a corresponding escape mechanism to synthesize their own proteins in the event of host protein synthesis shutdown and SG formation caused by eIF2α phosphorylation, and viruses can block the cell replication cycle through the PERK-eIF2α pathway, providing a favorable environment for their own replication. Subsequently, viruses can induce host cell autophagy or apoptosis through the eIF2α-ATF4-CHOP pathway. Conclusions This review summarizes the role of eIF2α in viral infection to provide a reference for studying the interactions between viruses and hosts.

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Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells

Cited by 15 publications

References 48 publications

Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation

The role of host eIF2α in viral infection

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