The inhibition of SLC8A1 promotes Ca2+-dependent cell death in Gastric Cancer

Abstract

Intracellular Ca²⁺ homeostasis dysregulation, through the modulation of calcium permeable ion channels and transporters, is gaining attention in cancer research as an apoptosis evasion mechanism. Recently, we highlighted a prognostic role for several calcium permeable channels. Among them, here, we focused on the plasma membrane bidirectional Na⁺/Ca²⁺ exchanger SLC8A1. Data from Kaplan-Meier plotter and The Cancer Genome Atlas were used to evaluate in silico the association of SLC8A1 expression with Gastric Cancer (GC) patients' survival, and its levels in different patient subgroups. In vitro experiments were used to explore SLC8A1 as a possible target in GC. Interestingly, SLC8A1 expression was associated with a worst prognosis, and resulted up-regulated in diffuse/poorly-cohesive histological GC type, Genomically Stable samples and in advanced TNM stages. We demonstrated that SLC8A1 selective pharmacological inhibition, through CB-DMB, significantly reduced cancer proliferation and induced Ca²⁺-dependent cell death in GC cells, both alone and synergically with cisplatin treatment. SLC8A1 inhibition could represents a potential subgroup-specific therapeutic approach for GC patients based on its ability to induce Ca²⁺-dependent cell death.

Keywords: Calcium-dependent cell death; Drug resistance; Gastric cancer; Patient-derived organoids; Plasma membrane calcium channel; Prognosis.