FRA-1: A key factor regulating signal transduction of tumor cells and a potential target molecule for tumor therapy

Zeng, Feng; He, Junyu; Jin, Xi; Liao, Qianjin; Chen, Zhifang; Peng, Honghua; Zhou, Yanhong

doi:10.1016/j.biopha.2022.113037

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…Fra-1 is a member of the FOS family and is an important nuclear transcription factor that regulates the growth, differentiation, and apoptosis of normal cells [ 6 , 7 , 19 – 21 ]. Fra-1 is highly expressed in a variety of malignant tumors and plays an important role in cell transformation, proliferation, invasion, and metastasis [ 18 – 21 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Fra-1 is an important nuclear transcription factor that regulates the growth, differentiation, and apoptosis of normal cells. It is abnormally expressed in many cancer cells and tissues, and plays an important role in the tumorigenesis and progression or maintenance of many tumor types [ 6 , 7 , 19 – 21 ]. Fra-1 levels are frequently elevated in a variety of human cancers because of carcinogenic signal transduction, and Fra-1 is closely related to metastasis and poor prognosis [ 20 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

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YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells

He¹,

Zeng²,

Jin³

et al. 2023

Oncology Research

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Fos-related antigen 1 (Fra-1) is a nuclear transcription factor that regulates cell growth, differentiation, and apoptosis. It is involved in the proliferation, invasion, apoptosis and epithelial mesenchymal transformation of malignant tumor cells. Fra-1 is highly expressed in gastric cancer (GC), affects the cycle distribution and apoptosis of GC cells, and participates in GC occurrence and development. However, the detailed mechanism of Fra-1 in GC is unclear, such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis. In this study, we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry. Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression, and affected GC cell proliferation. Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1 (HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells. Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation. These results will help to discover new molecular targets for the early diagnosis, treatment, and prognosis prediction of GC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells

He¹,

Zeng²,

Jin³

et al. 2023

Oncology Research

Self Cite

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“…Fra-1 was previously thought to be a non-viable target for pharmacological inhibition by small molecules, and as such most of the attempts to target the molecule focus on its destabilisation by inhibition of upstream kinases, or via targeting FOSL1 mRNA (Sobolev et al, 2022). Some metabolites and molecules are reported to non-specifically inhibit its expression and function, such as PARP1 inhibitors, glucocorticoid dexamethasone, Frontiers in Cell and Developmental Biology frontiersin.org ranpirnase and rosiglitazone, while vemurfanib and retinoic acid are shown to activate Fra-1 expression (Zeng et al, 2022). However, a few polypeptide and small molecule inhibitors against Fra-1 have demonstrated promise in recent years (reviewed in (Casalino et al, 2022) Table 6 and Figure 4).…”

Section: Ap-1 Familymentioning

confidence: 99%

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

Neuendorf

Simmons

Boyle

2023

Front. Cell Dev. Biol.

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The acquisition of resistance to anoikis, the cell death induced by loss of adhesion to the extracellular matrix, is an absolute requirement for the survival of disseminating and circulating tumour cells (CTCs), and for the seeding of metastatic lesions. In melanoma, a range of intracellular signalling cascades have been identified as potential drivers of anoikis resistance, however a full understanding of the process is yet to be attained. Mechanisms of anoikis resistance pose an attractive target for the therapeutic treatment of disseminating and circulating melanoma cells. This review explores the range of small molecule, peptide and antibody inhibitors targeting molecules involved in anoikis resistance in melanoma, and may be repurposed to prevent metastatic melanoma prior to its initiation, potentially improving the prognosis for patients.

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“…FRA-1 overexpression has been implicated in cancer cell proliferation, survival, migration, invasion, and plasticity in a large variety of neoplastic diseases, including most solid tumors. FRA-1 oncogenic roles have been discussed in a number of relevant reviews, dealing with many aspects of FRA-1 in tumorigenesis and metastasis mechanisms, along with recently proposed strategies of FRA-1 therapeutic targeting [28][29][30][31][50][51][52][53][54][55].…”

Section: Fra-1 In Tumorigenesismentioning

confidence: 99%

FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer

Casalino,

Talotta,

Matino

et al. 2023

IJMS

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Among FOS-related components of the dimeric AP-1 transcription factor, the oncoprotein FRA-1 (encoded by FOSL1) is a key regulator of invasion and metastasis. The well-established FRA-1 pro-invasive activity in breast cancer, in which FOSL1 is overexpressed in the TNBC (Triple Negative Breast Cancer)/basal subtypes, correlates with the FRA-1-dependent transcriptional regulation of EMT (Epithelial-to-Mesenchymal Transition). After summarizing the major findings on FRA-1 in breast cancer invasiveness, we discuss the FRA-1 mechanistic links with EMT and cancer cell stemness, mediated by transcriptional and posttranscriptional interactions between FOSL1/FRA-1 and EMT-regulating transcription factors, miRNAs, RNA binding proteins and cytokines, along with other target genes involved in EMT. In addition to the FRA-1/AP-1 effects on the architecture of target promoters, we discuss the diagnostic and prognostic significance of the EMT-related FRA-1 transcriptome, along with therapeutic implications. Finally, we consider several novel perspectives regarding the less explored roles of FRA-1 in the tumor microenvironment and in control of the recently characterized hybrid EMT correlated with cancer cell plasticity, stemness, and metastatic potential. We will also examine the application of emerging technologies, such as single-cell analyses, along with animal models of TNBC and tumor-derived CTCs and PDXs (Circulating Tumor Cells and Patient-Derived Xenografts) for studying the FRA-1-mediated mechanisms in in vivo systems of EMT and metastasis.

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FRA-1: A key factor regulating signal transduction of tumor cells and a potential target molecule for tumor therapy

Cited by 6 publications

References 51 publications

YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells

YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer

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