Identification of the Cysteine Protease Legumain as a Potential Chronic Hypoxia-Specific Multiple Myeloma Target Gene

Ada-Sophia Clees, Verena Stolp, Björn Häupl, Dominik C. Fuhrmann, Frank Wempe, Marcel Seibert, Sarah Weber, Antje Banning, Ritva Tikkanen, Richard Williams, Bernhard Brüne, Hubert Serve, Frank Schnütgen, Ivana von Metzler*, Nina Kurrle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
121 Downloads (Pure)

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1−6% O2), known as hypoxia. For MM cells, hypoxia is a physiologic feature that has been described to promote an aggressive phenotype and to confer drug resistance. However, studies on hypoxia are scarce and show little conformity. Here, we analyzed the mRNA expression of previously determined hypoxia markers to define the temporal adaptation of MM cells to chronic hypoxia. Subsequent analyses of the global proteome in MM cells and the stromal cell line HS-5 revealed hypoxia-dependent regulation of proteins, which directly or indirectly upregulate glycolysis. In addition, chronic hypoxia led to MM-specific regulation of nine distinct proteins. One of these proteins is the cysteine protease legumain (LGMN), the depletion of which led to a significant growth disadvantage of MM cell lines that is enhanced under hypoxia. Thus, herein, we report a methodologic strategy to examine MM cells under physiologic hypoxic conditions in vitro and to decipher and study previously masked hypoxia-specific therapeutic targets such as the cysteine protease LGMN.
Original languageEnglish
Pages (from-to)e292
JournalCells
Volume11
Issue number2
Early online date15 Jan 2022
DOIs
Publication statusEarly online date - 15 Jan 2022

Keywords

  • multiple myeloma
  • chronic hypoxia
  • asparaginyl endopepdidase (AEP)
  • legumain
  • glycolysis

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