Identification of cell type–specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors

Lebedev, Timofey; Khabusheva, Elmira; Mareeva, Sofia R; Ivanenko, Karina; Morozov, Alexey; Spirin, Pavel; Rubtsov, P. M.; Snezhkina, Anastasiya V.; Kudryavtseva, Anna V.; Sorokin, Maxim; Buzdin, Anton; Prassolov, Vladimir

doi:10.1016/j.jbc.2022.102226

Cited by 18 publications

(13 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, direct Erk1/2 inhibition might overcome resistance and escape mechanisms associated with its reactivation. RAH is a new oral Erk1/2 inhibitor, has a higher affinity toward Erk1/2, and shows lower toxicity than other drugs; its tolerability was proved in clinical studies . Experimental SAH is produced by the intracranial endovascular perforation method, which closely resembles clinical SAH on the causes of bleeding and physiological parameters and can induce long-term sensorimotor deficits and spatial learning deficits. − Similar to these reports, we observed that experimental SAH significantly induced long-term sensorimotor deficits using the MWM test and led to spatial learning deficits using the rotarod, foot fault, and forelimb placing tests.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2

Yang

Sun

et al. 2023

ACS Omega

View full text Add to dashboard Cite

Extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling has been shown to be involved in brain injury after subarachnoid hemorrhage (SAH). A first-in-human phase I study reported that ravoxertinib hydrochloride (RAH), a novel Erk1/2 inhibitor, has an acceptable safety profile and pharmacodynamic effects. Here, we showed that the level of Erk1/2 phosphorylation (p-Erk1/2) was significantly increased in the cerebrospinal fluid (CSF) of aneurysmal subarachnoid hemorrhage (aSAH) patients who developed poor outcomes. In a rat SAH model that was produced by the intracranial endovascular perforation method, western blot observed that the level of p-Erk1/2 was also increased in the CSF and basal cortex, showing a similar trend with aSAH patients. Immunofluorescence and western blot indicated that RAH treatment (i.c.v injection, 30 min post-SAH) attenuates the SAH-induced increase of p-Erk1/2 at 24 h in rats. RAH treatment can improve experimental SAH-induced long-term sensorimotor and spatial learning deficits that are evaluated by the Morris water maze, rotarod test, foot-fault test, and forelimb placing test. Moreover, RAH treatment attenuates neurobehavioral deficits, the blood−brain barrier damage, and cerebral edema at 72 h after SAH in rats. Furthermore, RAH treatment decreases the SAHelevated apoptosis-related factor active caspase-3 and the necroptosis-related factor RIPK1 expression at 72 h in rats. Immunofluorescence analysis showed that RAH attenuated neuronal apoptosis but not neuronal necroptosis in the basal cortex at 72 h after SAH in rats. Altogether, our results suggest that RAH improves long-term neurologic deficits through early inhibition of Erk1/2 in experimental SAH.

show abstract

Section: Discussionmentioning

confidence: 99%

RETRACTED: Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2

Yang

Sun

et al. 2023

ACS Omega

View full text Add to dashboard Cite

show abstract

“…The establishment of ERK-KTR reporter cell lines, as described in [ 29 , 30 ] allowed us to quantify ERK activity in individual live cells. The validation of the ERK activity reporter was recently described by us [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation

Bondarev

Ivanenko

Khabusheva

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Methionine dependence of malignant cells is one of the cancer hallmarks. It is well described that methionine deprivation drives cancer cells death, both in vitro and in vivo. Methionine gamma-lyase (MGL) isolated from different species or obtained by genetic engineering can be used for effective methionine depletion. In this work, we show that MGL S3, a genetically engineered protein comprised of MGL from Clostridium sporogenesis fused to epidermal growth factor (EGF)-like peptide, reduces, in vitro, the number of cancer cells of four different origins—neuroblastoma, lung, breast, and colon cancer. We reveal that MGL S3 is more toxic for neuroblastoma SH-SY5Y and lung cancer H1299 cells compared to MGL tetani, and causes cell death by the induction of apoptosis. In addition, the observed death of cells treated with MGL S3 is accompanied by the prominent downregulation of ERK activity. By the analysis of transcriptomic data of more than 1500 cancer cell lines and patient samples, we show that the high expression of four genes from the methionine metabolism pathway (AHCY, CBS, DNMT3A, and MTAP) is associated with poor prognosis for breast cancer and neuroblastoma patients. Additionally, cells of these origins are characterized by a high correlation between EGFR dependency and DNMT3A/CBS expression. Finally, we demonstrate the ability of MGL S3 to enhance the sensitivity of H1299 cells to EGFR inhibition with gefitinib.

show abstract

“…ERK1/2, one of the best-characterized members of MAPK family, mediates a wide range of cellular responses like gene expression, metabolism, motility, cell survival and death ( Wang et al, 2022 ). Substantial evidence exists that the phosphorylation of ERK1/2 could increase cell proliferation and cause an anti-apoptotic effect, thereby promoting the progression of tumor invasion and metastasis ( Lebedev et al, 2022 ; Wang et al, 2022 ). Conversely, suppression of ERK1/2 could effectively block many other extracellular signals that promote cell growth and movement, ultimately suppressing tumor invasion and metastasis ( Lebedev et al, 2022 ; Wang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Substantial evidence exists that the phosphorylation of ERK1/2 could increase cell proliferation and cause an anti-apoptotic effect, thereby promoting the progression of tumor invasion and metastasis (Lebedev et al, 2022;Wang et al, 2022). Conversely, suppression of ERK1/2 could effectively block many other extracellular signals that promote cell growth and movement, ultimately suppressing tumor invasion and metastasis (Lebedev et al, 2022;Wang et al, 2022). Hence, identification of small molecules that can inhibit ERK1/2 activity may be a useful Frontiers in Pharmacology frontiersin.org pharmacological strategy for the clinical treatment of numerous cancers (Lebedev et al, 2022;Wang et al, 2022).…”

Section: Hq Fmnt and Cs Significantly Inhibited The Erk1/2 And Pi3k-a...mentioning

confidence: 99%

“…Conversely, suppression of ERK1/2 could effectively block many other extracellular signals that promote cell growth and movement, ultimately suppressing tumor invasion and metastasis (Lebedev et al, 2022;Wang et al, 2022). Hence, identification of small molecules that can inhibit ERK1/2 activity may be a useful Frontiers in Pharmacology frontiersin.org pharmacological strategy for the clinical treatment of numerous cancers (Lebedev et al, 2022;Wang et al, 2022). In addition to ERK1/2, the PI3K-Akt signaling pathway also takes part in a variety of cellular activities, including cell growth, metabolism, motility, proliferation, survival, and apoptosis (Porta et al, 2014).…”

Section: Hq Fmnt and Cs Significantly Inhibited The Erk1/2 And Pi3k-a...mentioning

confidence: 99%

See 1 more Smart Citation

Uncovering the effects and molecular mechanism of Astragalus membranaceus (Fisch.) Bunge and its bioactive ingredients formononetin and calycosin against colon cancer: An integrated approach based on network pharmacology analysis coupled with experimental validation and molecular docking

Zhai

Tan

et al. 2023

Front. Pharmacol.

View full text Add to dashboard Cite

Colon cancer is a highly malignant cancer with poor prognosis. Astragalus membranaceus (Fisch.) Bunge (Huang Qi in Chinese, HQ), a well-known Chinese herbal medicine and a popular food additive, possesses various biological functions and has been frequently used for clinical treatment of colon cancer. However, the underlying mechanism is not fully understood. Isoflavonoids, including formononetin (FMNT) and calycosin (CS), are the main bioactive ingredients isolated from HQ. Thus, this study aimed to explore the inhibitory effects and mechanism of HQ, FMNT and CS against colon cancer by using network pharmacology coupled with experimental validation and molecular docking. The network pharmacology analysis revealed that FMNT and CS exerted their anticarcinogenic actions against colon cancer by regulating multiple signaling molecules and pathways, including MAPK and PI3K-Akt signaling pathways. The experimental validation data showed that HQ, FMNT and CS significantly suppressed the viability and proliferation, and promoted the apoptosis in colon cancer Caco2 and HT-29 cells. HQ, FMNT and CS also markedly inhibited the migration of Caco2 and HT-29 cells, accompanied by a marked increase in E-cadherin expression, and a notable decrease in N-cadherin and Vimentin expression. In addition, HQ, FMNT and CS strikingly decreased the expression of ERK1/2 phosphorylation (p-ERK1/2) without marked change in total ERK1/2 expression. They also slightly downregulated the p-Akt expression without significant alteration in total Akt expression. Pearson correlation analysis showed a significant positive correlation between the inactivation of ERK1/2 signaling pathway and the HQ, FMNT and CS-induced suppression of colon cancer. The molecular docking results indicated that FMNT and CS had a strong binding affinity for the key molecules of ERK1/2 signaling pathway. Conclusively, HQ, FMNT and CS exerted good therapeutic effects against colon cancer by mainly inhibiting the ERK1/2 signaling pathway, suggesting that HQ, FMNT and CS could be useful supplements that may enhance chemotherapeutic outcomes and benefit colon cancer patients.

show abstract

Identification of cell type–specific correlations between ERK activity and cell viability upon treatment with ERK1/2 inhibitors

Cited by 18 publications

References 60 publications

RETRACTED: Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2

RETRACTED: Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2

MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation

Uncovering the effects and molecular mechanism of Astragalus membranaceus (Fisch.) Bunge and its bioactive ingredients formononetin and calycosin against colon cancer: An integrated approach based on network pharmacology analysis coupled with experimental validation and molecular docking

Contact Info

Product

Resources

About