A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Braicu, Cornelia; Buse, Mihail; Busuioc, Constantin; Drula, Rares; Gulei, Diana; Ráduly, Lajos; Rusu, Alexandru Vasile; Irimie, Alexandru; Atanasov, Atanas G.; Slabý, Ondřej; Ionescu, Călin; Berindan‐Neagoe, Ioana

doi:10.3390/cancers11101618

Cited by 567 publications

(388 citation statements)

References 141 publications

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“…Simon et al (109) found that in oral cancer cells, ERK1/ERK2 activation inhibitors reduced the activity of ERK1/ERK2 while downregulating MMP-9 and reducing invasiveness. The activation of the ERK/MAPK signalling pathway can increase tumour invasion and metastasis by upregulating MMP expression, while inhibition of this signalling pathway can reduce tumour invasion and metastasis (110)(111). A previous study reported that mesothelin regulates the expression of MMP-7 through the MAPK/ERK signal transduction pathway, ERK1/2, AKT and JNK pathways, which enhances the invasiveness of ovarian cancer (112).…”

Section: Erk/mapk Signalling In Tumour Invasion and Metastasismentioning

confidence: 99%

ERK/MAPK signalling pathway and tumorigenesis (Review)

et al. 2020

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Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised. signalling elements that regulate basic processes including cell proliferation, differentiation and stress responses (1-3). These cascades transmit signals through sequential activation of three to five layers of protein kinases known as MAPK kinase kinase kinase (MAP4K), MAPK kinase kinase (MAP3K), MAPK kinase (MAPKK), MAPK and MAPK-activated protein kinases (MAPKAPK). The first three central layers are considered as a basic core unit, while the last two layers appear in some cascades and can vary among cells and stimuli. Four MAPK cascades have been defined based on the components in the MAPK layer: ERK1/2, c-Jun N-terminal kinase (JNK), p38 MAPK and ERK5. This review focuses on the ERK cascade (4-6) which involves several kinases in the MAP3K layer (mainly Rafs), including Ras/Raf/MAPK (MEK) 1/2 at the MAPKK layer, ERK1/2 at the MAPK layer and several MAPKAPKs in the next layer (ribosomal s6 kinases, MAP kinase-interacting serine/threonine-protein kinases, mitogen-and stress-activated protein kinases and cytosolic phospholipase A2). ERK cascades are highly regulated cascades that are responsible for basic cellular processes, including cell proliferation and differentiation. These regulatory factors affect bispecific phosphatases (7-10), scaffold proteins (11-14), signal duration and intensity (15), and the dynamic subcellular localization of cascade components (16,17). Due to the importance of the ERK cascade, ERK disorders are harmful to cells and ultimately to the body. Excessive activation of upstream proteins and kinases in the ERK pathway has been shown to induce various diseases, including cancer, inflammation, developmental disorders and neurological disorders (18-22). Since ERK1 and ERK2 are very similar, the singular form of ERK is used in this review, although two subtypes exist. Dysfunction in the Ras-ERK pat...

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Section: Erk/mapk Signalling In Tumour Invasion and Metastasismentioning

confidence: 99%

ERK/MAPK signalling pathway and tumorigenesis (Review)

et al. 2020

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“…35 MAPKs are a family of serine/threonine kinases that transmit extracellular signals in response to specific intracellular signaling via the ERK, p38 MAPK and JNK pathways. 36 Activation of the JNK and p38 MAPK is necessary for programmed cell death, and ERKs are related to cancer cell proliferation and resistance to apoptosis. 37 The p38 MAPK pathway is triggered by environmental stress, inflammatory cytokines, and various mitogens.…”

Section: Dovepressmentioning

confidence: 99%

<p>Fucoidan Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma via the p38 MAPK/ERK and PI3K/Akt Signal Pathways</p>

Duan

Xue

et al. 2020

CMAR

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Purpose: Fucoidan is a natural bioactive product with broad therapeutic applications. Hepatocellular carcinoma (HCC) is a common malignancy of the liver associated with a relatively high mortality rate; thus, effective treatments are urgently needed. Here, the effects of fucoidan on HCC and the underlying mechanism were explored. Methods: The proliferation and apoptosis of two HCC cell lines (BEL-7402 and LM3) treated with different concentrations of fucoidan or saline were assessed. The levels of proliferating cell nuclear antigen (PCNA) and CCK8 assay were used to determine proliferative capabilities of BEL-7402 and LM3 cells. Apoptosis of LM3 cells was assessed by Hoechst 33342 staining, Western blotting and flow cytometry. The capability of fucoidan to inhibit the growth of LM3 cells was investigated by monitoring of the p38 MAPK/ERK pathways and the upstream kinases, PI3K/Akt. LM3 xenograft tumors were used for in vivo verification. Results: Cell proliferation and apoptosis assays consistently showed that fucoidan has an inhibitory effect on cell growth. Fucoidan significantly promoted apoptosis of LM3 cells through a mechanism involving activation of caspases 8, 9, and 3 accompanied by changes in B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax), as well as changes in the phosphorylation of p38 MAPK and ERK. Fucoidan also altered the phosphorylation of its upstream kinase, Akt. Fucoidan treatment markedly reduced the growth of LM3 xenograft tumors, consistent with the in vitro results. Conclusion: Fucoidan conveys antitumor effects and, thus, should be further explored as a potential treatment option for HCC.

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“…IGF-1 bound activated IGF-1R phosphorylates insulin receptor substrates (such as IRS1, IRS2 and Shc). The Src homology 2 (SH2) domains of these substrates are recognized by signaling molecules to activate the intracellular effectors such as RAS, RAF and SOS and the RAS/MAPK pathway [36,37]. Interestingly, in our previous study, we observed significant downregulation of NRAS with miR-29a overexpression in PDAC cell lines [38].…”

Section: Igf-1 Belonging To the Igf Family Members Is One Of The Kementioning

confidence: 84%

Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

Dey

Liu

Factora

et al. 2020

Preprint

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease.Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. MethodsIn this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing hPSC cells and controls. Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top candidate miR-29a targets in hPSC cells transfected with miR-29a mimic or scramble control. ResultsRNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs.Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. ConclusionsTogether, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-tumor cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies. 4

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A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Cited by 567 publications

References 141 publications

ERK/MAPK signalling pathway and tumorigenesis (Review)

ERK/MAPK signalling pathway and tumorigenesis (Review)

<p>Fucoidan Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma via the p38 MAPK/ERK and PI3K/Akt Signal Pathways</p>

Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

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