ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy. - 2024
ATP1A1; Bufalin; Cardiotonic steroid; Melanoma; Resistance; Sodium pump; Oncology; Genetics; Cancer Research
Abstract :
[en] Despite advancements in treating metastatic melanoma, many patients exhibit resistance to targeted therapies. Our study focuses on ATP1A1, a sodium pump subunit associated with cancer development. We aimed to assess ATP1A1 prognostic value in melanoma patients and examine the impact of its ligand, bufalin, on melanoma cell lines in vitro and in vivo. High ATP1A1 expression (IHC) correlated with reduced overall survival in melanoma patients. Resistance to BRAF inhibitor was linked to elevated ATP1A1 levels in patient biopsies (IHC, qPCR) and cell lines (Western blot, qPCR). Additionally, high ATP1A1 mRNA expression positively correlated with differentiation/pigmentation markers based on data from The Cancer Genome Atlas (TCGA) databases and Verfaillie proliferative gene signature analysis. Bufalin specifically targeted ATP1A1 in caveolae, (proximity ligation assay) and influenced Src phosphorylation (Western blot), thereby disrupting multiple signaling pathways (phosphokinase array). In vitro, bufalin induced apoptosis in melanoma cell lines by acting on ATP1A1 (siRNA experiments) and, in vivo, significantly impeded melanoma growth using a nude mouse xenograft model with continuous bufalin delivery via an osmotic pump. In conclusion, our study demonstrates that ATP1A1 could serve as a prognostic marker for patient survival and a predictive marker for response to BRAF inhibitor therapy. By targeting ATP1A1, bufalin inhibited cell proliferation, induced apoptosis in vitro, and effectively suppressed tumor development in mice. Thus, our findings strongly support ATP1A1 as a promising therapeutic target, with bufalin as a potential agent to disrupt its tumor-promoting activity.
Disciplines :
Oncology
Author, co-author :
Soumoy, Laura; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium. laura.soumoy@umons.ac.be ; Institut National de la Santé et de la Recherche Médicale (INSERM) U981, Gustave Roussy Cancer Campus, Villejuif, France. laura.soumoy@umons.ac.be
Genbauffe, Aline ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory ; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium
Mouchart, Lena; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium
Sperone, Alexandra; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium
Trelcat, Anne; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium
Mukeba-Harchies, Léa; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium
Wells, Mathilde; Laboratory of Pharmaceutical Analysis, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium
Blankert, Bertrand; Laboratory of Pharmaceutical Analysis, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium
Najem, Ahmad; Laboratory of Clinical and Experimental Oncology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1000, Brussels, Belgium
Ghanem, Ghanem; Laboratory of Clinical and Experimental Oncology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1000, Brussels, Belgium
Saussez, Sven; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium ; Department of Otolaryngology and Head and Neck Surgery, CHU Saint-Pierre, 1000, Brussels, Belgium
Journe, Fabrice; Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons (UMONS), 7000, Mons, Belgium. fabrice.journe@umons.ac.be ; Laboratory of Clinical and Experimental Oncology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1000, Brussels, Belgium. fabrice.journe@umons.ac.be
Language :
English
Title :
ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy.
We thank “Les amis de l’Institut Bordet” from the Jules Bordet Institute (Brussels, Belgium) and the Botalys company and Nicolas Houyoux.This work was supported by the University of Mons, the Health Institute of the University of Mons, the FRMH, “Les amis de l’Institut Bordet” from the Jules Bordet Institute (Brussels, Belgium) and the Botalys company for the in vivo part.
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