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Hoeger, Birgit; Nadolni, Wiebke; Hampe, Sarah; Hoelting, Kilian; Fraticelli, Marco; Zaborsky, Nadja; Madlmayr, Anna; Sperrer, Viktoria; Fraticelli, Laura; Addington, Lynda; Steinritz, Dirk; Chubanov, Vladimir; Geisberger, Roland; Greil, Richard; Breit, Andreas; Boekhoff, Ingrid; Gudermann, Thomas; Zierler, Susanna

Inactivation of TRPM7 Kinase Targets AKT Signaling and Cyclooxygenase-2 Expression in Human CML Cells

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  • Media type: E-Article
  • Title: Inactivation of TRPM7 Kinase Targets AKT Signaling and Cyclooxygenase-2 Expression in Human CML Cells
  • Contributor: Hoeger, Birgit; Nadolni, Wiebke; Hampe, Sarah; Hoelting, Kilian; Fraticelli, Marco; Zaborsky, Nadja; Madlmayr, Anna; Sperrer, Viktoria; Fraticelli, Laura; Addington, Lynda; Steinritz, Dirk; Chubanov, Vladimir; Geisberger, Roland; Greil, Richard; Breit, Andreas; Boekhoff, Ingrid; Gudermann, Thomas; Zierler, Susanna
  • Published: Oxford University Press (OUP), 2023
  • Published in: Function, 4 (2023) 6
  • Language: English
  • DOI: 10.1093/function/zqad053
  • ISSN: 2633-8823
  • Keywords: Cancer Research ; Cell Biology ; Molecular Medicine ; Physiology
  • Origination:
  • Footnote:
  • Description: Abstract Cyclooxygenase-2 (COX-2) is a key regulator of inflammation. High constitutive COX-2 expression enhances survival and proliferation of cancer cells, and adversely impacts antitumor immunity. The expression of COX-2 is modulated by various signaling pathways. Recently, we identified the melastatin-like transient-receptor-potential-7 (TRPM7) channel-kinase as modulator of immune homeostasis. TRPM7 protein is essential for leukocyte proliferation and differentiation, and upregulated in several cancers. It comprises of a cation channel and an atypical α-kinase, linked to inflammatory cell signals and associated with hallmarks of tumor progression. A role in leukemia has not been established, and signaling pathways are yet to be deciphered. We show that inhibiting TRPM7 channel-kinase in chronic myeloid leukemia (CML) cells results in reduced constitutive COX-2 expression. By utilizing a CML-derived cell line, HAP1, harboring CRISPR/Cas9-mediated TRPM7 knockout, or a point mutation inactivating TRPM7 kinase, we could link this to reduced activation of AKT serine/threonine kinase and mothers against decapentaplegic homolog 2 (SMAD2). We identified AKT as a direct in vitro substrate of TRPM7 kinase. 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 wildtype phenotype. Inhibition of TRPM7 resulted in reduced phosphorylation of AKT and diminished COX-2 expression in peripheral blood mononuclear cells derived from CML patients, and reduced proliferation in patient-derived CD34+ cells. These results highlight a role of TRPM7 kinase in AKT-driven COX-2 expression and suggest a beneficial potential of TRPM7 blockade in COX-2-related inflammation and malignancy.
  • Access State: Open Access