PERK Integrates Oncogenic Signaling and Cell Survival During Cancer Development

Bu, Yiwen; Diehl, J. Alan

doi:10.1002/jcp.25336

Cited by 65 publications

(46 citation statements)

References 101 publications

(134 reference statements)

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“…IRESs were found to be activated in tumor cells continually subjected to diverse stress conditions of the tumor microenvironment [32, 33]. Furthermore, accumulating evidence argues for the presence of chronic stress of endoplasmic reticulum or unfolded protein response (UPR) in different types of cancers, including breast cancer (for a recent review, see [34]). Given the preferential shift towards cap-independent mRNA translation during UPR [35], we hypothesized that endoplasmic reticulum stress might stimulate the translation of open-reading frames downstream of the major initiation codon.…”

Section: Resultsmentioning

confidence: 99%

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

et al. 2016

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BackgroundTo date, all studies conducted on breast cancer diagnosis have focused on the expression of the full-length 66-kDa estrogen receptor alpha (ERα66). However, much less attention has been paid to a shorter 46-kDa isoform (ERα46), devoid of the N-terminal region containing the transactivation function AF-1. Here, we investigated the expression levels of ERα46 in breast tumors in relation to tumor grade and size, and examined the mechanism of its generation and its specificities of coregulatory binding and its functional activities.MethodsUsing approaches combining immunohistochemistry, Western blotting, and proteomics, antibodies allowing ERα46 detection were identified and the expression levels of ERα46 were quantified in 116 ERα-positive human breast tumors. ERα46 expression upon cellular stress was studied, and coregulator bindings, transcriptional, and proliferative response were determined to both ERα isoforms.ResultsERα46 was expressed in over 70% of breast tumors at variable levels which sometimes were more abundant than ERα66, especially in differentiated, lower-grade, and smaller-sized tumors. We also found that ERα46 can be generated via internal ribosome entry site-mediated translation in the context of endoplasmic reticulum stress. The binding affinities of both unliganded and fully-activated receptors towards co-regulator peptides revealed that the respective potencies of ERα46 and ERα66 differ significantly, contributing to the differential transcriptional activity of target genes to 17β estradiol (E2). Finally, increasing amounts of ERα46 decrease the proliferation rate of MCF7 tumor cells in response to E2.ConclusionsWe found that, besides the full-length ERα66, the overlooked ERα46 isoform is also expressed in a majority of breast tumors. This finding highlights the importance of the choice of antibodies used for the diagnosis of breast cancer, which are able or not to detect the ERα46 isoform. In addition, since the function of both ERα isoforms differs, this work underlines the need to develop new technologies in order to discriminate ERα66 and ERα46 expression in breast cancer diagnosis which could have potential clinical relevance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0780-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

et al. 2016

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“…Thus it is likely that the protein-folding and post-translational capacity of the ER is stretched by the considerably increased production of collagens which is enlisted following tRNA i Met upregulation, and if so, this would elicit ER stress responses and other cell signalling pathways known to relay information from the ER to the nucleus. Indeed, ER stress is well-established to influence transcriptional programmes that lead to metastasis (Bu and Diehl, 2016), and it will be interesting to determine whether this is in part responsible for connecting increased tRNA i Met 's levels to the metastatic capacity of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

et al. 2016

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The cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, the level of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts has been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus, specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis.

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“…ER stress can be induced by oncogene activation, such as B-Raf proto-oncogene mutations, H-Ras proto-oncogene mutations, and c-Myc amplification, as well as chemotherapeutic drugs [21]. When the ER functions, only correctly folded proteins can reach their cell compartment and unfolded or misfolded proteins accumulate within the ER 14 BioMed Research International lumen.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Prognostic Values of MANF Expression in Hepatocellular Carcinoma

Liu

et al. 2020

BioMed Research International

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and its prognosis is still poor. Mesencephalic astrocyte-derived neurotrophic factor (MANF) plays a key role in endoplasmic reticulum stress. ER stress plays a key role in HCC carcinogenesis. To confirm the clinical and prognostic value of MANF in HCC, we investigated the expression level of MANF in HCC as recorded in databases, and the results were verified by experiment. Survival analysis was probed by the Kaplan–Meier method. Cox regression models were used to ascertain the prognostic value of MANF in HCC tissue microarray. The diagnostic value of MANF in HCC was evaluated by receiver operating characteristic curve analysis. Potential correlation between MANF and selected genes was also analyzed. Results showed that MANF was overexpressed in HCC. Patients with high MANF expression levels had a worse prognosis and higher risk of tumor recurrence. Furthermore, the expression level of MANF had good diagnostic power. Correlation analysis revealed potential regulatory networks of MANF in HCC, laying a foundation for further study of the role of MANF in tumorigenesis. In conclusion, MANF was overexpressed in HCC and related to the occurrence and development of HCC. It is a potential diagnostic and prognostic indicator of HCC.

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PERK Integrates Oncogenic Signaling and Cell Survival During Cancer Development

Cited by 65 publications

References 101 publications

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

Diagnostic and Prognostic Values of MANF Expression in Hepatocellular Carcinoma

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