Expression and function of FRA1 protein in tumors

Jiang, Xingming; Xie, Hui; Dou, Yingyu; Yuan, Jing; Zeng, Da; Xiao, Songshu

doi:10.1007/s11033-019-05123-9

Cited by 60 publications

(60 citation statements)

References 144 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3a), suggesting that ASN007 is a potent inhibitor of ERK signaling. In previous reports, FRA1 directly regulated the expression of cell cycle-related protein, thereby promoting cell proliferation [16,17]. In line with previous results, ASN007 decreased expression of cell-cycle-related proteins such as FoxM1, Aurora A, PLK1, Cyclin D1, and Cyclin B1 in all EGFR-TKI-resistant cells (Fig.…”

Section: Asn007 Induces Cell Cycle Arrest Through Fra1 Regulationsupporting

confidence: 90%

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

Ku¹,

Heo²,

Kim³

et al. 2021

Preprint

View full text Add to dashboard Cite

The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Thus, development of effective strategies to overcome resistance to EGFR-TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR-TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR-TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR-TKIs synergistically decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR-TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR-TKIs by overcoming acquired resistance.

show abstract

Section: Asn007 Induces Cell Cycle Arrest Through Fra1 Regulationsupporting

confidence: 90%

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

Ku¹,

Heo²,

Kim³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, AKT activity in CAFs, mediated through the actin-binding protein Girdin, has been shown to enhance lung tumorigenesis (104). Downstream of p38 is the AP1 transcription factor complex, which is a dimer that can be comprised of members of the FOS, JUN, ATF, and MAF families, with FRA1 belonging to the FOS family (105). AP1 has long been associated with cellular responses to stress (activated by MAP kinases such as p38) and inflammatory signals (106).…”

Section: Discussionmentioning

confidence: 99%

Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

et al. 2021

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identifi ed Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1 + cancer-associated fi broblasts (CAF) support PDAC survival, through a NetG1mediated effect on glutamate/glutamine metabolism. Also, NetG1 + CAFs are intrinsically immunosuppressive and inhibit natural killer cell-mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE:This study demonstrates the feasibility of targeting a fi broblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.

show abstract

“…The transcription and expression of Fra1 were reported to be increased after stimulation with mitogenic growth factors, including EGF, hepatocyte growth factor and insulin-like growth factor 1. Activation of ERK1/2 signaling is considered one of the most critical types of upstream signaling of Fra1 after treatment with mitogenic growth factors (37). Of note, Fra1 is highly expressed in K-Ras-driven cancer cells (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Xanthohumol targets the ERK1/2‑Fra1 signaling axis to reduce cyclin D1 expression and inhibit non‑small cell lung cancer

Gao¹,

Li²,

Zhou

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

High expression of cyclin D1 has a crucial role in the maintenance of unlimited cell growth in human cancer cells. The present study indicated that cyclin D1 was overexpressed in human non-small cell lung cancer (NSCLC) tumor tissues and cell lines. Knockout of cyclin D1 suppressed NSCLC cell growth, colony formation and in vivo tumor growth. Of note, the natural product xanthohumol (Xanth) inhibited NSCLC cells via the downregulation of cyclin D1. A further mechanistic study revealed that Xanth suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1 (Fra1), which eventually inhibited the transcriptional activity of activator protein-1 and decreased the mRNA level of cyclin D1. Furthermore, suppression of ERK1/2 impaired Fra1 phosphorylation and enhanced Xanth-induced Fra1 ubiquitination and degradation. In addition, the S265D mutation compromised Xanth-induced Fra1 degradation. Finally, the in vivo anti-tumor effect of Xanth was validated in a xenograft mouse model. In summary, the present results indicated that targeting ERK1/2-Fra1-cyclin D1 signaling is a promising anti-tumor strategy for NSCLC treatment.

show abstract

Expression and function of FRA1 protein in tumors

Cited by 60 publications

References 144 publications

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Xanthohumol targets the ERK1/2‑Fra1 signaling axis to reduce cyclin D1 expression and inhibit non‑small cell lung cancer

Contact Info

Product

Resources

About

Expression and function of FRA1 protein in tumors

Cited by 60 publications

References 144 publications

ERK&nbsp;Inhibitor ASN007&nbsp;Effectively Overcomes Acquired Resistance to EGFR&nbsp;Inhibitor in Non-small Cell Lung Cancer

ERK&nbsp;Inhibitor ASN007&nbsp;Effectively Overcomes Acquired Resistance to EGFR&nbsp;Inhibitor in Non-small Cell Lung Cancer

Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Xanthohumol targets the ERK1/2‑Fra1 signaling axis to reduce cyclin D1 expression and inhibit non‑small cell lung cancer

Contact Info

Product

Resources

About

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer