Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1

Feng, Yuxiong; Jin, Dexter X.; Sokol, Ethan S.; Reinhardt, Ferenc; Miller, Daniel; Gupta, Piyush B.

doi:10.1038/s41467-017-01052-y

Cited by 108 publications

(106 citation statements)

References 51 publications

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“…Thus, whereas translation reprogramming is clearly associated with cancer progression (Sendoel et al, 2017), how changes in the translation of specific mRNAs lead cells to undergo a proliferative-to-invasive phenotypic transition is only beginning to be understood. For example, PERK's pro-metastatic function in breast cancer has been attributed in part to activation of the transcription factor CREB3L1/OASIS (Feng et al, 2017). Interestingly, translation of the EMT-associated transcription factors SNAIL1, TWIST, and ZEB2 is promoted by YB-1, an RNA-binding protein and transcription factor that plays a pleiotropic role in cancer progression (Lasham et al, 2013), which, like eIF2a phosphorylation, also suppresses global cap-dependent translation (Evdokimova et al, 2009).…”

Section: Translation Reprogramming and Invasionmentioning

confidence: 99%

Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming

García-Jiménez

Goding

2019

Cell Metabolism

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Considerable progress has been made in identifying microenvironmental signals that effect the reversible phenotypic transitions underpinning the early steps in the metastatic cascade. However, although the general principles underlying metastatic dissemination have been broadly outlined, a common theme that unifies many of the triggers of invasive behavior in tumors has yet to emerge. Here we discuss how many diverse signals that induce invasion converge on the reprogramming of protein translation via phosphorylation of eIF2a, a hallmark of the starvation response. These include starvation as a consequence of nutrient or oxygen limitation, or pseudo-starvation imposed by cell-extrinsic microenvironmental signals or by cell-intrinsic events, including oncogene activation. Since in response to resource limitation single-cell organisms undergo phenotypic transitions remarkably similar to those observed within tumors, we propose that a starvation/pseudo-starvation model to explain cancer progression provides an integrated and evolutionarily conserved conceptual framework to understand the progression of this complex disease. Glutamine, the most abundant amino acid in the blood (Brosnan, 2003), can be depleted in tumors (Kamphorst et al., 2015;Pan et al., 2016;Roberts et al., 1956), most likely as a result of it being used to fuel anabolic metabolism (Altman et al., 2016; DeBerardinis et al.

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Section: Translation Reprogramming and Invasionmentioning

confidence: 99%

Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming

García-Jiménez

Goding

2019

Cell Metabolism

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“…For example, overexpression of XBP1 could promote cell invasion and metastasis by upregulating MMP9 in ESCC [28]. Similarly, PERK also contributes to ECM reorganization in breast cancer and overexpression of ATF4, which is a component of PERK pathway, induces cell invasion and metastasis, stimulating MMP2 and MMP7 expression in ESCC [13]. These evidences suggest that UPR activation might be relevant for the development of tumor metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, endoplasmic reticulum (ER) stress is believed to contribute to several steps along with the metastasis and proliferation process of various types of cancers. For example, ER proteins such as XBP1, PERK, ATF6and ATF4 involved in ER stress have been reported to be participate in tumor growth and metastasis [12][13][14][15]. However, the underlying mechanisms responsible for metastasis and proliferation of TC are still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma

Zhao

Kang

Xun

et al. 2020

Preprint

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Background: Thyroid cancer (TC) is the most common type of endocrine malignancy tumor and the incidence of it is increasing over years. Conventional surgery, radiotherapy and chemotherapy are difficult to improve the significant effects of it due to aggression and metastasis of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), which are regarded as the most malignant type of TC. Glucose-regulated protein (GRP78) is the key molecule of tumor growth, apoptosis and metastasis. However, the underlying mechanisms of GRP78 on TC still require discussion. This study aimed to explore the role of GRP78 and its potential mechanism in TC.Results: GRP78 expression was increased in TC tissues when compared with adjacent normal tissues. Besides, down-regulation of GRP78 significantly inhibited the metastatic and proliferative ability of ATC cells in in vitro studies. In addition, tunicamycin-induced ER stress up-regulated the expression of GRP78, PERK and XBP1 as well as reversed the metastatic ability of GRP78 in ATC cells. Bioinformatics and statistical analysis of gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for RNA-sequencing data from si-GRP78 and si-control showed that GRP78 might regulate the ability of metastasis through extracellular matrix (ECM) remodeling in ATC cells, as well as the expression of ECM components such as COL1A1 and MMP13 were shown to be highly relevant to ATC. The analysis of GEPIA database confirmed high genomic amplification of MMP13 and COL1A1 in TC tissues and showed correlation with TNM stage. Further western blotting analysis showed that MMP13 might be the target of GRP78 in ATC cells and ER stress could activate the expression of MMP13 that was suppressed by the GRP78 depletion.Conclusions: GRP78 acts as an important regulator of metastasis under ER stress. In addition, the function of GRP7 might be mediated by ECM remodeling in ATC cells, implicating it as a therapeutic target in TC.

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“…*, P Ͻ 0.05; **, P Ͻ 0.01. inhibits PKR when expressed by the EUs11 virus (44,49,50). Another possibility is that ΔN146 may abrogate eIF2␣ phosphorylation mediated by PERK or GCN2, both of which are often activated under oncogenic stress in tumor cells (41,42,51,52). An additional possibility is to block the antiviral action of interferon-stimulated genes, such as IFIT1, IFIT3, Rsad2 (viperin), and Mx2.…”

Section: Discussionmentioning

confidence: 99%

“…3C and D, levels of expression of eIF2␣ were comparable in mock-and virusinfected cells. Interestingly, phosphorylated eIF2␣ was presented in mock-infected cells, which is presumably due to oncogenic stress (41,42). While wild-type virus inhibited eIF2␣ phosphorylation, Δ␥ 1 34.5 aggravated its phosphorylation.…”

mentioning

confidence: 98%

Selective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant Cells

Xing

2019

J Virol

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Oncolytic herpes simplex virus 1 (HSV-1), devoid of the γ134.5 gene, exerts antitumor activities. However, the oncolytic effects differ, ranging from pronounced to little responses. Although viral and host factors are involved, much remains to be deciphered. Here we report that engineered HSV-1 ΔN146, bearing amino acids 147 to 263 of γ134.5, replicates competently in and lyses malignant cells refractory to the γ134.5 null mutant. Upon infection, ΔN146 precludes phosphorylation of translation initiation factor eIF2α (α subunit of eukaryotic initiation factor 2), ensuring viral protein synthesis. On the other hand, ΔN146 activates interferon (IFN) regulatory factor 3 (IRF3) and IFN expression, known to prime immunity against virus and tumor. Nevertheless, ΔN146 exhibits sustained replication even exposed to exogenous IFN-α. In a 4T1 tumor model, ΔN146 markedly reduces tumor growth and metastasis formation. This coincides with viral replication or T cell infiltration in primary tumors. ΔN146 is undetectable in normal tissues in vivo. Targeted HSV-1 editing results in a unique antineoplastic agent that enables inflammation without major interference of viral growth within tumor cells. IMPORTANCE Oncolytic herpes simplex virus 1 is a promising agent for cancer immunotherapy. Due to a complex virus-host interaction, less is clear about what viral signature(s) constitutes a potent oncolytic backbone. Through molecular or genetic dissection, we showed that selective editing of the γ134.5 gene enables viral replication in malignant cells, activation of transcription factor IRF3, and subsequent induction of type I IFN. This translates into profoundly reduced primary tumor growth and metastasis burden in an aggressive breast carcinoma model in vivo. Our work reveals a distinct oncolytic platform that is amendable for further development.

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Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1

Cited by 108 publications

References 51 publications

Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming

Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming

Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma

Selective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant Cells

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