Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer

Olea-Flores, Monserrat; Zuñiga-Eulogio, Miriam Daniela; Mendoza-Catalán, Miguel Ángel; Rodríguez-Ruiz, Hugo Alberto; Castañeda-Saucedo, Eduardo; Ortuño-Pineda, Carlos; Padilla‐Benavides, Teresita; Navarro-Tito, Napoleón

doi:10.3390/ijms20122885

Cited by 112 publications

(73 citation statements)

References 237 publications

(402 reference statements)

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“…The MEK-ERK pathway is a central driver of (TGF-β-induced) EMT in cancer [30,31] and required for cell migration and invasion in PDAC-derived cells [32]. To analyze the role of ERK activation in RAC1B-mediated control of epithelial and mesenchymal gene expression, we treated Panc1-RAC1B knockdown cells in the absence or presence of TGF-β1 with the MEK inhibitor U0126 and determined the expression of CDH1 and SNAI1.…”

Section: Inhibition Of Mek-erk Signaling By Rac1b Underlies Its Stimumentioning

confidence: 99%

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Zinn

Otterbein

Lehnert

et al. 2019

Cells

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The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown to potently inhibit transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition (EMT) in pancreatic and breast epithelial cells, but the underlying mechanism has remained obscure. Using a panel of pancreatic ductal adenocarcinoma (PDAC)-derived cell lines of different differentiation stages, we show that RAC1B is more abundantly expressed in well differentiated as opposed to poorly differentiated cells. Interestingly, RNA interference-mediated knockdown of RAC1B decreased expression of the epithelial marker protein E-cadherin, encoded by CDH1, and enhanced its TGF-β1-induced downregulation, whereas ectopic overexpression of RAC1B upregulated CDH1 expression and largely prevented its TGF-β1-induced silencing of CDH1. Conversely, knockdown of RAC1B, or deletion of the RAC1B-specific exon 3b by CRISPR/Cas-mediated genomic editing, enhanced basal and TGF-β1-induced upregulation of mesenchymal markers like Vimentin, and EMT-associated transcription factors such as SNAIL and SLUG. Moreover, we demonstrate that knockout of RAC1B enhanced the cells’ migratory activity and derepressed TGF-β1-induced activation of the mitogen-activated protein kinase ERK2. Pharmacological inhibition of ERK1/2 activation in RAC1B-depleted cells rescued cells from the RAC1B knockdown-induced enhancement of cell migration, TGF-β1-induced downregulation of CDH1, and upregulation of SNAI1. We conclude that RAC1B promotes epithelial gene expression and suppresses mesenchymal gene expression by interfering with TGF-β1-induced MEK-ERK signaling, thereby protecting cells from undergoing EMT and EMT-associated responses like acquisition of cell motility.

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Section: Inhibition Of Mek-erk Signaling By Rac1b Underlies Its Stimumentioning

confidence: 99%

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Zinn

Otterbein

Lehnert

et al. 2019

Cells

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“…Phosphorylation of ERK1/2 has been reported to activate pro-survival pathways inducing anti-apoptotic proteins such as BCL2, and downregulation of p53 in breast, cervical, and hepatocellular carcinoma [30,52]. Interestingly, we found decreased ERK1/2 phosphorylation mainly in the 5-FU treatment and AS+5-FU, as well as an unexpected increase in the use of Trimethylglycine, which may indicate that administration of this adjuvant favors the ERK1/2 activity as reported in the primary cultures of human osteoblasts [53]; this, however, contends with data reported in lipid metabolism in which the use of Trimethylglycine decreased ERK1/2 phosphorylation [54].…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of proteins related with DNA repair and inhibition of apoptosis are the most frequent alterations found in cancer with low rates of treatment response [29]. Extracellular signal-regulated kinases 1 and 2 (ERK 1/2), (also known as mitogen activated protein kinases MAPK p44 and p42), regulate cell division, apoptosis, and motility [30]. In vitro studies indicate that phosphorylation of ERK proteins has a negative effect in the response to 5-FU based chemotherapy [31].…”

Section: Stat6 Inhibition Plus 5-fu Modulates the Expression Of Protementioning

confidence: 99%

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

Mendoza

Sánchez-Barrera

Callejas

et al. 2020

IJMS

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Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial–mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as β-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-β, and Il-17a, critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.

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“…The MAPK pathway includes the signaling protein kinases RET, ERK, JNK and MEK, participating in the control of cell proliferation, differentiation and metastasis [35,36]. Some studies have addressed the result that MAPK signaling increase the levels of EMT-related transcription factors, whereas the decrease in E-cadherin expression can cause EMT [37,38]. On that account, Western blot analysis assess the MAPK signaling cascades and downstream signaling to reveal metastasis mechanism of PTC.…”

Section: Discussionmentioning

confidence: 99%

KIFC1 accelerates the proliferation, migration and invasion of papillary thyroid cancer cells via MAPK signaling

Nie¹,

Han²,

Wen³

et al. 2020

Preprint

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Kinesin family member C1 (KIFC1) acts as a kind of minus end-directed motorized protein and is considered as an oncogene of some cancer types. However, no studies have fully elucidated its biological activity and molecular mechanisms in papillary thyroid cancer (PTC). The study focused on reporting the overexpression of KIFC1 in cell lines and tissues of PTC. Moreover, clinicopathological features analysis showed that KIFC overexpression is significantly correlated with extrathyroidal invasion and lymph node metastasis. Knockdown of KIFC1 significantly reduced cell growth, migration and invasion in PTC cells, and concomitant increased levels of differentiation markers, such as Tg and Nis. Knockdown of KIFC1 markedly increased the expression level of epithelial cell marker (E-cadherin), and decreased the expression levels of epithelial-mesenchymal transition (EMT) related transcriptional factor N-cadherin, Snail and ZEB1. Further study revealed that knockdown of KIFC1 downregulated stemness markers ALDH2 and SOX2, and inhibited the MAPK signaling cascades and downstream signaling, including p-ERK, ERK, p-JNK, JNK, MMP2, and MMP9, which can affect the expression of the EMT associated factors. Taken together, we reported that KIFC1 might promoted the proliferation, migration and invasion of PTC cells and offer a candidate molecular target for therapeutic intervention.

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Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer

Cited by 112 publications

References 237 publications

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

KIFC1 accelerates the proliferation, migration and invasion of papillary thyroid cancer cells via MAPK signaling

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