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Potentiating Cell Death in Multiple Myeloma Cells: Focus on Regulation of ALK2 Activity

By: Jenna Carter, PhD
Posted: Wednesday, March 8, 2023

An article published in Cell Communication and Signaling highlighted the use of an immunosuppressive drug to increase bone morphogenic protein (BMP) activity and induce cell death in myeloma cells. Toril Holien, PhD, of the Norwegian University of Science and Technology-NTNU, Trondheim, and colleagues treated multiple myeloma cell lines with FK506 and other FKBP-binding compounds and assessed cell viability and proliferation. Their findings revealed potentiated apoptosis in multiple myeloma cell lines treated with FK506.

“Multiple myeloma cells are sensitive to BMP-induced apoptosis and growth arrest. Increasing BMP activity in bone marrow to reduce tumor growth and promote bone formation could thus be beneficial for myeloma patients. Here we show that the immunosuppressive drug FK506 potentiated SMAD1/5/8 activation via the TGF-β/BMP type I receptor ALK2 and thereby increased myeloma cell death,” stated Dr. Holien and colleagues.

The human myeloma cell lines INA-6, IH-1, KJON, and KARPAS-417 (ECACC, #06100302) were used in this study. Additionally, the stomach cancer cell line KATO-III (ATCC) and the B-cell lymphoma cell line DOHH-2 (DSMZ) were also used. Cell viability, proliferation, and apoptosis assays were performed to assess the effects of FK506 on myeloma cells. Additionally, siRNA, shRNA, and CRISPR/Cas9 technology were used to characterize the functional receptor complex involved in inducing the ALK2-SMAD1/5/8 activation seen in INA-6 cells.

Overall findings revealed that the combination of FK506 with BMP6 strongly potentiated the activation of SMAD1/5/8 as measured by relative luciferase activity. Receptor affinity assays and siRNA-targeting profiles indicated that the FK506-potentiated ALK2-SMAD1/5/8 activation was induced via removal of FKBP12. Additional findings suggested that this FK506-potentiated ALK2 activity may be due in part to switching a possible nonsignaling complex into an active signaling complex. Based on this, study authors concluded that targeting FKBP12 with a suitable nonimmunosuppressive compound may be a novel treatment option to increase BMP activity.

Disclosure: The study authors reported no conflicts of interest.

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