2022
Volume 22, Number 3/4, pp. 52-54
Sigma-1 receptor could participate in Rac-dependent oncogenesis through modulation of macrophage activity
N. Natsvlishvili, L. Shanshiashvili and D. Mikeladze
Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili Ave, 0162 Tbilisi, Georgia
I. Beritashvili Centre of Experimental Biomedicine, 14 Gotua St, 0160 Tbilisi, Georgia
The sigma-1 receptor (Sig1R) is a membrane chaperone protein found in the mammalian nervous system, peripheral tissues and immune systems. Studies have shown that sigma receptors are highly expressed in various human tumour cells, and treating these cells with sigma ligands leads to effects such as rounding, detachment and growth inhibition. However, whether Sig1R protects cancer cells from death through its chaperoning activity has yet to be addressed. On a different note, overexpression of metabotropic glutamate receptor 1/5 (mGluR1/5) in non-neuronal cells has been associated with cancer progression. mGluR1/5 is prominently expressed in intracellular membranes like the endoplasmic reticulum (ER), mitochondria and nuclear membranes. To explore the role of mGluR1/5 in the Sig1R-dependent association with partner proteins like the small GTP-binding protein Rac and the inositol trisphosphate receptor (IP3R), we conducted a transfection experiment, introducing mGluR5 cDNAs into macrophages. Our findings revealed that overexpressed mGluR5 diminishes the binding between Sig1R and IP3R and changes the lipopolysaccharide-dependent association of mGluR1/5 with Rac. These results suggest that intracellular glutamate receptors may form part of a large protein complex in the ER of macrophages. Activation of intracellular mGluR5 with high glutamate levels could lead to the dissociation of Sig1R from IP3R and its subsequent association with Rac. Additionally, the association between Sig1R and Rac may trigger the activation of downstream effectors such as Pak and NOX, leading to actin rearrangement and the production of reactive oxygen species. These disruptions alter macrophage phenotypes, may contribute to immunosuppression, and ultimately facilitate the progression of tumorigenesis.