Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism

García-Ortega, María Belén; López, Gabriel; Jiménez, Gema; Garcı́a-Garcı́a, Javier; Conde, V.; Boulaiz, Houría; Carrillo, Esmeralda; Perán, Macarena; Marchal, Juan Antonio; García, María Ángel

doi:10.1017/erm.2017.11

Cited by 31 publications

(40 citation statements)

References 118 publications

(170 reference statements)

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“…The levels of PKR mRNA expression could not be associated to chemotherapy response in our analysis. The Ser/Thr kinase PKR is a non-canonical kinase involved in many cellular pathways exerting various functions on cell growth and tumorigenesis [4,7,8]. Although there have been multiple studies of PKR, the exact role in cancer biology remains controversial.…”

Section: Discussionmentioning

confidence: 99%

“…Although there have been multiple studies of PKR, the exact role in cancer biology remains controversial. This is due on one hand to its ability to induce eIF2α-mediated apoptosis and on the other hand to NF-κB-mediated pro-survival effect, involved in both tumour-suppressive or oncogenic roles [6][7][8]11,14]. Because we previously identified PKR as a molecular target of 5-FU in several colon cancer cells lines [14] playing an important role in the cytotoxic effect of 5-FU, through the induction of apoptosis, in a PKR expression-dependent manner, we expected a high expression level of the PKR gene in responder patients.…”

Section: Discussionmentioning

confidence: 99%

“…However, the high level of post-translational modifications and regulation of the protein indicated that PKR activity does not necessarily have to correspond to the amount of its messenger RNA. In fact, numerous proteins have been described as regulating their activity (e.g., PACT, trans-activation response (TAR) RNA binding protein (TRBP), nucleophosmin (NPM)) [4,7,8,[46][47][48] and several post-translational modifications have been showed by SUMOylation and ISGylation, among others [49,50]. Nc886 has been described as a PKR inhibitor, being the inhibition of PKR/NF-kB in correlation with its tumour suppressor activity.…”

Section: Discussionmentioning

confidence: 99%

“…The role of PKR as a cellular stress response protein is widely known, as PKR intervenes against numerous and varied infections, also eliminating damaged cells inducing apoptosis. In addition, PKR is able to allow the cells to live via NF-kB activation once the stress has been resolved on time [4,7,8,13]. Moreover, PKR also regulates some tumour suppressors and protein kinases involved in cancer pathways such as the signal transducers and activators of transcription factors (STATs), activating transcription factors (ATFs), tumour suppressor p53 (Tp53), the phosphatase and tensin homologue tumour suppressor (PTEN), the mitogen-activated protein kinases (MAPKs), and the toll-like receptors (TLRs), among others [4,7,8,13].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, PKR is able to allow the cells to live via NF-kB activation once the stress has been resolved on time [4,7,8,13]. Moreover, PKR also regulates some tumour suppressors and protein kinases involved in cancer pathways such as the signal transducers and activators of transcription factors (STATs), activating transcription factors (ATFs), tumour suppressor p53 (Tp53), the phosphatase and tensin homologue tumour suppressor (PTEN), the mitogen-activated protein kinases (MAPKs), and the toll-like receptors (TLRs), among others [4,7,8,13]. All these data suggest how important it is that PKR is expressed at adequate levels in normal tissue where it would be slightly regulated, as well as the importance that PKR would have in tumours where, regardless of its expression, its regulation can be critical.…”

Section: Discussionmentioning

confidence: 99%

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Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Ortega-García

Mesa

Moya

et al. 2020

Cancers

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Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients' data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR Cancers 2020, 12, 379 2 of 17 mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Ortega-García

Mesa

Moya

et al. 2020

Cancers

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EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Kuipers

Mandemakers

et al. 2020

Annals of Neurology

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Objective The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. Methods Methods consisted of genome‐wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. Results We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR‐mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon‐inducible double‐stranded RNA‐dependent protein kinase activator A), the product of another gene causing monogenic dystonia. Interpretation We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485–497

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Knockdown of EIF2AK2-OAS1 axis reduces ATP production inducing AMPK phosphorylation to inhibit the malignant behavior of gastric cancer cells

Lai,

Wang,

et al. 2024

J Bioenerg Biomembr

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Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism

Cited by 31 publications

References 118 publications

Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Knockdown of EIF2AK2-OAS1 axis reduces ATP production inducing AMPK phosphorylation to inhibit the malignant behavior of gastric cancer cells

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