Inactivation of TRPM7 kinase targets AKT signaling and cyclooxygenase-2 expression in human CML cells

Abstract

Abstract Cyclooxygenase-2 (COX-2) is a key regulator of inflammation. High constitutive COX-2 expression enhances survival and proliferation of tumor cells, whereas it adversely impacts anti-tumor immunity. We recently identified the melastatin-like transient-receptor-potential-7 (TRPM7) protein as modulator of immune homeostasis. TRPM7 is essential for leukocyte proliferation and differentiation, and upregulated in several cancer tissues. It combines a cation channel with an α-kinase, which is linked to inflammatory cell responses, and associated with hallmarks of tumor progression. A role in leukemia is not established. Here, we show that inhibiting TRPM7 in CML patient cells results in reduced constitutive COX-2 expression and cell proliferation. Using the CML-derived cell line HAP1 harboring CRISPR/Cas9-mediated TRPM7 knockout or a point mutation inactivating TRPM7 kinase, we could link this defect to reduced AKT activation. Pharmacologic blockade of TRPM7 in wildtype HAP1 cells confirmed the effect on COX-2 via altered AKT signaling. Addition of an AKT activator on TRPM7 kinase-dead cells reconstituted the phenotype. Inhibition of TRPM7 resulted in reduced COX-2 expression in peripheral blood mononuclear cells derived from CML patients, and diminished patient-derived CD34+ cell proliferation. We highlight a role of TRPM7 kinase in AKT-driven COX-2 expression, and suggest a beneficial potential of TRPM7 blockade in COX-2-directed chemotherapy.