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.
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http://dx.doi.org/10.1186/s12935-023-03196-y | DOI Listing |
Pathol Res Pract
December 2024
Department of Pathology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Background: Patients with high-grade serous carcinoma (HGSC) are commonly diagnosed at late disease stages and after primary tumors have disseminated in the peritoneum. The overexpression of tight junction proteins has been associated with poor prognosis in this setting, potentially reflecting the tumor´s adaptive changes in the disease cascade.
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Eur J Cancer
November 2024
University of Perugia, Unit of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
A unique collaboration of multi-disciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to two-centimeter safety margins. For a correct stage classification and treatment decision, a sentinel lymph node biopsy shall be offered in patients with tumor thickness ≥ 1.
View Article and Find Full Text PDFBMC Health Serv Res
December 2024
Open Medical Ltd, London, UK.
Background: The UK's National Health Service (NHS) is grappling with rising demand and limited dermatologists, leading to longer waiting times. This is particularly concerning for conditions like malignant melanoma, where early diagnosis is crucial. Teledermatology is being introduced to address these issues, but its impact on patients' monetary and time costs, especially in deprived areas, is under-researched.
View Article and Find Full Text PDFCancer Lett
December 2024
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, USA; Enzyme by Design Inc., Chicago, USA; Research Biologist, Biological Science Research and Development, Department of Veterans Affairs Medical Center, Chicago, Illinois, USA. Electronic address:
L-asparaginase (L-ASNase) is crucial in treating pediatric acute lymphoblastic leukemia (ALL), but its use is hampered by side effects from the immunogenicity and L-glutaminase (L-GLNase) co-activity of FDA-approved bacterial L-ASNases, often leading to treatment discontinuation and poor outcomes. The toxicity of these L-ASNases makes them especially challenging to use in adult cancer patients. To overcome these issues, we developed EBD-200, a humanized guinea pig L-ASNase with low Km and no L-GLNase activity, eliminating glutamine-related toxicity.
View Article and Find Full Text PDFAm J Clin Dermatol
December 2024
Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), Heidelberg University, NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
Melanoma, a highly aggressive form of skin cancer, has seen significant advancements in treatment through the introduction of immunotherapy. However, the variability in patient responses underscores the need for reliable biomarkers to guide treatment decisions. This article reviews key biomarkers in melanoma immunotherapy, such as PD-L1 expression, tumor mutational burden (TMB), and gene expression profiles (GEPs).
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