BRAF and NRAS mutated melanoma: Different Ca2+ responses, Na+/Ca2+ exchanger expression, and sensitivity to inhibitors

Author(s)

Esteves, Gabriela Nohemi Nunez ^[1] ; Ferraz, Leticia Silva ^[1] ; Alvarez, Marcela Maciel Palacio ^[2] ; da Costa, Claudia Alves ^[3] ; Lopes, Rayssa de Mello ^[3] ; Tersariol, Ivarne Luis dos Santos ^[2] ; Rodrigues, Tiago ^[1]

Affiliation

^[1] Univ Fed ABC UFABC, Ctr Ciencias Nat & Humanas CCNH, Santo Andre, SP - Brazil

^[2] Univ Fed Sao Paulo Unifesp, Escola Paulista Med EPM, Dept Bioquim, Sao Paulo, SP - Brazil

^[3] Univ Mogi das Cruzes UMC, Ctr Interdisciplinar Invest Bioquim CIIB, Mogi Das Cruzes, SP - Brazil

• Document type: Journal article
• Source: Cell Calcium; v. 90, SEP 2020.
• Web of Science Citations: 0

Abstract

Calcium is a ubiquitous intracellular second messenger, playing central roles in the regulation of several biological processes. Alterations in Ca2+ homeostasis and signaling are an important feature of tumor cells to acquire proliferative and survival advantages, which include structural and functional changes in storage capacity, channels, and pumps. Here, we investigated the differences in Ca2+ homeostasis in vemurafenib-responsive and non-responsive melanoma cells. Also, the expression of the Na+/Ca2+ exchanger (NCX) and the impact of its inhibition were studied. For this, it was used B-RAF(V600E) and NRAS(Q61R)-mutated human melanoma cells. The intracellular Ca2+ chelator BAPTA-AM decreased the viability of SK-MEL-147 but not of SK-MEL-19 and EGTA sensitized NRAS(Q61R )-mutated cells to vemurafenib. These cells also presented a smaller response to thapsargin and ionomycin regarding the cytosolic Ca2+ levels in relation to SK-MEL-19, which was associated to an increased expression of NCX1, NO basal levels, and sensitivity to NCX inhibitors. These data highlight the differences between B-RAF(V600E) and NRAS(Q61R)-mutated melanoma cells in response to Ca2+ stimuli and point to the potential combination of clinically used chemotherapeutic drugs, including vemurafenib, with NCX inhibitors as a new therapeutic strategy to the treatment of melanoma. (AU)

• FAPESP's process: 18/25747-5 - Alterations of mitochondrial morphology and dynamics in cancer: understanding of tumor biology and prospecting new therapeutic targets
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/07367-5 - Investigation of Phenothiazine-Induced Cell Death Mechanisms In Tumor Cells: Changes in Gene Expression, Role of Bcl-2 Family Proteins, and ER Stress
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/03964-6 - Glycosaminoglycans and proteoglycans: interplay between structure and function
• Grantee: Helena Bonciani Nader
• Support Opportunities: Research Projects - Thematic Grants