دورية أكاديمية
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FGFR2-triggered autophagy and activation of Nrf-2 reduce breast cancer cell response to anti-ER drugs.

التفاصيل البيبلوغرافية
العنوان: FGFR2-triggered autophagy and activation of Nrf-2 reduce breast cancer cell response to anti-ER drugs.
المؤلفون: Gorska-Arcisz M; Laboratory of Enzymology and Molecular Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland., Popeda M; Department of Pathomorphology, Medical University of Gdansk, Gdansk, Poland., Braun M; Department of Pathology, Chair of Oncology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland., Piasecka D; Laboratory of Enzymology and Molecular Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland., Nowak JI; Department of Histology, Medical University of Gdansk, Gdansk, Poland., Kitowska K; Laboratory of Enzymology and Molecular Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland., Stasilojc G; Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland., Okroj M; Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland., Romanska HM; Department of Pathology, Chair of Oncology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland. hanna.romanska@gmail.com., Sadej R; Laboratory of Enzymology and Molecular Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211, Gdansk, Poland. rafal.sadej@gumed.edu.pl.
المصدر: Cellular & molecular biology letters [Cell Mol Biol Lett] 2024 May 14; Vol. 29 (1), pp. 71. Date of Electronic Publication: 2024 May 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 9607427 Publication Model: Electronic Cited Medium: Internet ISSN: 1689-1392 (Electronic) Linking ISSN: 14258153 NLM ISO Abbreviation: Cell Mol Biol Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: 2016- : London : BioMed Central
Original Publication: Wrocław, Poland : Dept. of Genetic Biochemistry, Institute of Biochemistry, University of Wrocław, 1996-
مواضيع طبية MeSH: Autophagy*/drug effects , Breast Neoplasms*/genetics , Breast Neoplasms*/metabolism , Breast Neoplasms*/drug therapy , Breast Neoplasms*/pathology , Kelch-Like ECH-Associated Protein 1*/metabolism , Kelch-Like ECH-Associated Protein 1*/genetics , NF-E2-Related Factor 2*/metabolism , NF-E2-Related Factor 2*/genetics , Receptor, Fibroblast Growth Factor, Type 2*/metabolism , Receptor, Fibroblast Growth Factor, Type 2*/genetics, Female ; Humans ; Cell Line, Tumor ; MCF-7 Cells ; Sequestosome-1 Protein/metabolism ; Sequestosome-1 Protein/genetics ; Signal Transduction/drug effects ; Estrogen Antagonists/pharmacology ; Estrogen Receptor Modulators/pharmacology
مستخلص: Background: Genetic abnormalities in the FGFR signalling occur in 40% of breast cancer (BCa) patients resistant to anti-ER therapy, which emphasizes the potential of FGFR-targeting strategies. Recent findings indicate that not only mutated FGFR is a driver of tumour progression but co-mutational landscapes and other markers should be also investigated. Autophagy has been recognized as one of the major mechanisms underlying the role of tumour microenvironment in promotion of cancer cell survival, and resistance to anti-ER drugs. The selective autophagy receptor p62/SQSTM1 promotes Nrf-2 activation by Keap1/Nrf-2 complex dissociation. Herein, we have analysed whether the negative effect of FGFR2 on BCa cell response to anti-ER treatment involves the autophagy process and/or p62/Keap1/Nrf-2 axis.
Methods: The activity of autophagy in ER-positive MCF7 and T47D BCa cell lines was determined by analysis of expression level of autophagy markers (p62 and LC3B) and monitoring of autophagosomes' maturation. Western blot, qPCR and proximity ligation assay were used to determine the Keap1/Nrf-2 interaction and Nrf-2 activation. Analysis of 3D cell growth in Matrigel® was used to assess BCa cell response to applied treatments. In silico gene expression analysis was performed to determine FGFR2/Nrf-2 prognostic value.
Results: We have found that FGFR2 signalling induced autophagy in AMPKα/ULK1-dependent manner. FGFR2 activity promoted dissociation of Keap1/Nrf-2 complex and activation of Nrf-2. Both, FGFR2-dependent autophagy and activation of Nrf-2 were found to counteract the effect of anti-ER drugs on BCa cell growth. Moreover, in silico analysis showed that high expression of NFE2L2 (gene encoding Nrf-2) combined with high FGFR2 expression was associated with poor relapse-free survival (RFS) of ER+ BCa patients.
Conclusions: This study revealed the unknown role of FGFR2 signalling in activation of autophagy and regulation of the p62/Keap1/Nrf-2 interdependence, which has a negative impact on the response of ER+ BCa cells to anti-ER therapies. The data from in silico analyses suggest that expression of Nrf-2 could act as a marker indicating potential benefits of implementation of anti-FGFR therapy in patients with ER+ BCa, in particular, when used in combination with anti-ER drugs.
(© 2024. The Author(s).)
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معلومات مُعتمدة: UMO-2017/27/B/NZ3/01474 National Science Center, Poland; UMO-2020/39/B/NZ4/02696 National Science Center, Poland; UMO-2020/37/N/NZ3/01401 Natonal Science Center, Poland
فهرسة مساهمة: Keywords: Autophagy; FGFR2; Keap1; Luminal breast cancer; Nrf-2; p62
المشرفين على المادة: 0 (Kelch-Like ECH-Associated Protein 1)
0 (NF-E2-Related Factor 2)
EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 2)
0 (Sequestosome-1 Protein)
0 (Estrogen Antagonists)
0 (Estrogen Receptor Modulators)
تواريخ الأحداث: Date Created: 20240514 Date Completed: 20240515 Latest Revision: 20240717
رمز التحديث: 20240717
مُعرف محوري في PubMed: PMC11092031
DOI: 10.1186/s11658-024-00586-6
PMID: 38745155
قاعدة البيانات: MEDLINE
الوصف
تدمد:1689-1392
DOI:10.1186/s11658-024-00586-6