Targeting Calcium Signalling in Malignant Mesothelioma

Abstract

Calcium ions (Ca²⁺) are central in cancer development and growth, serving as a major signaling system determining the cell's fate. Therefore, the investigation of the functional roles of ion channels in cancer development may identify novel approaches for determining tumor prognosis. Malignant mesothelioma is an aggressive cancer that develops from the serosal surface of the body, strictly related to asbestos exposure. The treatment of malignant mesothelioma is complex and the survival outcomes, rather than the overall survival data are, to date, disappointedly daunting. Nevertheless, conventional chemotherapy is almost ineffective. The alteration in the expression and/or activity of Ca²⁺ permeable ion channels seems to be characteristic of mesothelioma cells. In this review, we explore the involvement of the Ca²⁺toolkit in this disease. Moreover, the established sensitivity of some Ca²⁺channels to selective pharmacological modulators makes them interesting targets for mesothelioma cancer therapy.

Keywords: Ca2+ channel; Ca2+ toolkit; Cancer; Mesothelioma; Signalling pathway.

Figure 1

Examples of Ca²⁺-permeable channels, pumps, and plasma membrane and intracellular organelles exchangers. Ca²⁺ entry from the extracellular space is mediated by plasma membrane channels including Transient Receptor Potential channel (TRP ) and Voltage-Gated Ca²⁺ Channel (VGCC), and the plasma membrane transporters such as NCX (Na⁺/Ca²⁺ exchanger) and PMCA (Plasma Membrane Ca²⁺-ATPase) allow for the removal of Ca²⁺ from the cytoplasm. Upon the depletion of internal Ca²⁺ stores, a particular way of Ca²⁺ entry is through the store-operated calcium entry (SOCE) channels, Orai1 (Ca²⁺ release-activated Ca²⁺ modulator 1), and STIM (Stromal Interaction Molecule). The movement of Ca²⁺ toward intracellular stores and the cytoplasm occurs by intracellular calcium channels and transporters as well as endoplasmic reticulum channels, IP₃R (Inositole 3 Phosphate Receptor) and RyR (Ryanodine Receptor), and transporters, SERCA (Sarco/Endoplasmic Reticulum Ca²⁺-ATPase); mitochondrial transporter, MCU (Mitochondrial Ca²⁺ Uniporter) and channels, VDAC1 (Voltage Dependent Anion Channel 1); and lysosomal channel, TPC (Two-porte channel).