Glutaminase inhibition in multiple myeloma induces apoptosis via MYC degradation
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Madlen Effenberger1, Kathryn S. Bommert1, Viktoria Kunz1, Jessica Kruk1, Ellen Leich2, Martina Rudelius2, Ralf Bargou1 and Kurt Bommert1
1Comprehensive Cancer Center Mainfranken University Hospital Würzburg, Würzburg, Germany
2Institute of Pathology and Comprehensive Cancer Center Mainfranken University of Würzburg, Würzburg, Germany
Kurt Bommert, email: [email protected]
Keywords: multiple myeloma, MYC, glutaminase
Received: January 17, 2017 Accepted: May 04, 2017 Published: August 24, 2017
Multiple Myeloma (MM) is an incurable hematological malignancy affecting millions of people worldwide. As in all tumor cells both glucose and more recently glutamine have been identified as important for MM cellular metabolism, however there is some dispute as to the role of glutamine in MM cell survival. Here we show that the small molecule inhibitor compound 968 effectively inhibits glutaminase and that this inhibition induces apoptosis in both human multiple myeloma cell lines (HMCLs) and primary patient material. The HMCL U266 which does not express MYC was insensitive to both glutamine removal and compound 968, but ectopic expression of MYC imparted sensitivity. Finally, we show that glutamine depletion is reflected by rapid loss of MYC protein which is independent of MYC transcription and post translational modifications. However, MYC loss is dependent on proteasomal activity, and this loss was paralleled by an equally rapid induction of apoptosis. These findings are in contrast to those of glucose depletion which largely affected rates of proliferation in HMCLs, but had no effects on either MYC expression or viability. Therefore, inhibition of glutaminolysis is effective at inducing apoptosis and thus serves as a possible therapeutic target in MM.
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