Double-Stranded RNA-Dependent Protein Kinase Regulates the Motility of Breast Cancer Cells

Xu, Mei; Chen, Gang; Wang, Siying; Liao, Mingjun; Frank, Jacqueline A.; Bower, Kimberly A.; Zhang, Zhuo; Shi, Xianglin; Luo, Jia

doi:10.1371/journal.pone.0047721

Cited by 10 publications

(12 citation statements)

References 43 publications

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“…Similarly, kisspeptin-mediated EIF2AK2 activation was demonstrated to be required for the kisspeptin-induced suppression of the migratory and invasive capabilities of cancer cells. The present results are in accordance with a previous study reporting the implication of EIF2AK2 in the regulation of breast cancer cell migration (23). Therefore, it may be hypothesized that EIF2AK2 can be activated by kisspeptin, and kisspeptin regulates cancer cell motility via EIF2AK2-mediated signaling pathways.…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies have proposed a role for EIF2AK2 in the regulation of cytoskeletal dynamics (23,26), which appear to be similar to the roles of kisspeptin in the regulation of cellular architecture (7,8,13). However, whether kisspeptin may inhibit cancer cell migration and invasion through the modulation of EIF2AK2 has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 71%

“…It has previously been reported that invasive ductal carcinoma cells exhibit increased EIF2AK2 expression levels compared with adjacent normal breast tissue (21); however, the expression and activity levels of EIF2AK2 have been negatively correlated with the metastatic capabilities of breast cancer cells (22). Furthermore, the double-stranded RNA-mediated activation of EIF2AK2 has been implicated in the regulation of breast cancer cell motility (23). These results suggest that EIF2AK2 activity may be critical for the suppression of cancer metastasis.…”

Section: Introductionmentioning

confidence: 85%

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Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2

Kim¹,

Cho²

2017

Molecular Medicine Reports

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Kisspeptin is a protein encoded by the KISS1 gene, which has been reported to suppress the metastatic capabilities of various types of cancer cells, through the activation of its G‑protein coupled receptor GPR54. However, the molecular mechanisms underlying the involvement of kisspeptin‑mediated signaling in the inhibition of cancer cell migration and invasion have yet to be elucidated. The present in vitro cell proliferation, migration and invasion assays and in vivo experimental metastasis studies demonstrated that kisspeptin‑induced eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) activation suppressed the metastatic capabilities of several types of cancer cells. Kisspeptin was revealed to inhibit the migratory and invasive abilities of highly metastatic breast SK‑BR‑3, prostatic PC‑3 and colorectal adenocarcinoma LoVo human cancer cell lines, whereas its inhibitory effects were abolished following the silencing of EIF2AK2 expression using RNA interference. Similarly, kisspeptin failed to inhibit the migration and invasion of mouse embryonic fibroblasts following the deletion of the EIF2AK2 gene. Furthermore, kisspeptin was demonstrated to activate Ras homolog gene family member A (RhoA)‑dependent signaling, and to phosphorylate EIF2AK2 via RhoA‑mediated pathways in various cancer cells. In addition, results obtained from nude mice bearing LoVo‑derived xenograft tumors revealed that kisspeptin inhibited tumor growth through an EIF2AK2‑dependent mechanism, and an in vivo metastasis assay identified kisspeptin‑activated EIF2AK2 signaling as critical for the suppression of distant metastasis. The present study concluded that kisspeptin represses cancer metastasis via EIF2AK2 signaling, thus clarifying the role of kisspeptin signaling in complicated cancer metastasis signaling network. Therefore, kisspeptin treatment may be a choice for blocking metastases.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 85%

See 1 more Smart Citation

Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2

Kim¹,

Cho²

2017

Molecular Medicine Reports

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“…In addition to its translational regulatory function, PKR has a role in signal transduction and transcriptional control through the inhibition of κB (IκB)/nuclear factor κB (NF-κB) pathways2425. Furthermore, PKR is involved in various other pathways that activate and engage a number of transcription factors controlling the expression of multiple genes, including interferon regulatory factor 1 (IRF-1), signal transducers and activators of transcription factors (STATs), mitogen-activated protein kinases (MAPKs), and p532326272829. PKR can directly stimulate cell growth through NF-κB pathways and the p38 MAPK3031.…”

Section: Discussionmentioning

confidence: 99%

Zebularine upregulates expression of CYP genes through inhibition of DNMT1 and PKR in HepG2 cells

Nakamura

Aizawa

Aung

et al. 2017

Sci Rep

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Drug-induced hepatotoxicity is one of the major reasons cited for drug withdrawal. Therefore, it is of extreme importance to detect human hepatotoxic candidates as early as possible during the drug development process. In this study, we aimed to enhance hepatocyte functions such as CYP gene expression in HepG2 cells, one of the most extensively used cell lines in evaluating hepatotoxicity of chemicals and drugs. We found that zebularine, a potent inhibitor of DNA methylation, remarkably upregulates the expression of CYP genes in HepG2 cells. In addition, we revealed that the upregulation of CYP gene expression by zebularine was mediated through the inhibition of both DNA methyltransferase 1 (DNMT1) and double-stranded RNA-dependent protein kinase (PKR). Furthermore, HepG2 cells treated with zebularine were more sensitive than control cells to drug toxicity. Taken together, our results show that zebularine may make HepG2 cells high-functioning and thus could be useful for evaluating the hepatotoxicity of chemicals and drugs speedily and accurately in in-vitro systems. The finding that zebularine upregulates CYP gene expression through DNMT1 and PKR modulation sheds light on the mechanisms controlling hepatocyte function and thus may aid in the development of new in-vitro systems using high-functioning hepatocytes.The liver is essential for maintaining normal physiology and homeostasis of the body. Among its multiple critical roles, the metabolism of chemicals, toxins and drugs by hepatocytes is especially important. Abnormality in homeostasis is often associated with hepatotoxicity 1 . Therefore, a simple and rapid method of assaying a substance's potential for liver damage is needed to predict the toxicity and adverse effects of chemicals for pathophysiological and toxicological purposes 2 . Many preliminary hepatotoxicity studies have been carried out using in-vivo and/or in-vitro animal models, but we should not rely too heavily on such models because of species differences, animal protection concerns and model accuracy issues. Thus more reliable and more practical human in-vitro cell culture models are needed to improve the effectiveness with which we can evaluate the human hepatotoxicity of substances as well as reduce the number of animals used during each drug's development process. In-vitro models using human cells derived from the liver, such as primary hepatocytes and hepatoma cell lines, are preferred 3 . Various sources of hepatic tissue, including whole or partial livers from organ donors or cadavers and resected liver tissue from therapeutic hepatectomies or small surgical biopsies, have been used to generate human hepatocyte cultures4 . Yet hepatocytes originating from these sources sometimes exhibit lower cell viability in culture because they come from diseased livers (e.g., cirrhotic livers) or are damaged during the handling process. Furthermore, it is difficult to guarantee a ready supply of freshly isolated human hepatocytes, and primary human hepatocytes are known to rapidly lose cellular fu...

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“…Além de sua função regulatória na tradução de proteínas, a PKR tem um papel na transdução de sinais e no controle transcricional através do inibidor das vias κB (IkB) / fator nuclear κB (NF-kB) (Gil et al, 2000;Gil et al, 2004 (Williams, 2001;Garcia et al, 2006;Xu et al, 2012). A enzima possui dois domínios bem caracterizados consistindo de um segmento terminal regulatório NH2, onde se encontram as sequências de ligação de RNAd, e o domínio catalítico serina/treonina na terminação carboxílica (Forman, 1990a;b;Dickinson et al, 2003).…”

Section: Introductionunclassified

Efeito do tratamento quimioterápico sobre a ação da proteína quinase dependente de RNA (PKR) nos sistemas nociceptivo e muscular

Carvalho¹

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Double-Stranded RNA-Dependent Protein Kinase Regulates the Motility of Breast Cancer Cells

Cited by 10 publications

References 43 publications

Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2

Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2

Zebularine upregulates expression of CYP genes through inhibition of DNMT1 and PKR in HepG2 cells

Efeito do tratamento quimioterápico sobre a ação da proteína quinase dependente de RNA (PKR) nos sistemas nociceptivo e muscular

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