Glutaminase inhibition in multiple myeloma induces apoptosisviaMYC degradation

Abstract

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.

Plasma cells: You are what you eat

“…209 Under normal circumstances, long-lived plasma cells use glucose mainly for antibody glycosylation, and to a lesser extent for ATP. 211 This may be another key difference between MM and normal long-lived plasma cells, since as mentioned above, genetic ablation of glutaminolysis has not revealed obvious defects in plasma cell numbers or secretion thus far. Furthermore, glycolysis can activate MCL1, an anti-apoptotic factor promoting myeloma survival.…”

“…Inhibition of glutaminolysis results in MM death. 211 This may be another key difference between MM and normal long-lived plasma cells, since as mentioned above, genetic ablation of glutaminolysis has not revealed obvious defects in plasma cell numbers or secretion thus far. c-Myc is an important factor contributing to the tumorigenic phenotype of MM cells and enhances expression of glutamine transporters as well as favoring glutaminolysis.…”

“…23,105 Thus, the dependence on aerobic glycolysis in MM is a marked shift from the normal metabolic phenotype of long-lived plasma cells and is likely to promote the malignant transformation of these cells. 211,212 In addition to being a key source of fuel, glutamine uptake also triggers the mTOR pathway and stimulates cell proliferation through a STAT3-dependent mechanism. 210 Despite the importance of glucose in the metabolism of MM cells, the transporter responsible for its uptake is inconsistent between human and mouse cell lines.…”

“…c-Myc is an important factor contributing to the tumorigenic phenotype of MM cells and enhances expression of glutamine transporters as well as favoring glutaminolysis. 211,212 In addition to being a key source of fuel, glutamine uptake also triggers the mTOR pathway and stimulates cell proliferation through a STAT3-dependent mechanism. 213 Glutamine also can upregulate HIF1α and can possibly mediate survival of the tumor cell under conditions of hypoxia, a condition typically associated with the MM bone marrow.…”

Therapeutic Approaches Targeting Glucose, Glutamine and Lipid Metabolism in Multiple Myeloma

“…ASCT2 inhibitörlerinin tedaviye yönelik olarak kullanılması; mTORC1 aktivitesinin baskılanması, hücre çoğalması, otofaji ve protein sentezindeki meydana getirdiği değişiklikler nedeniyle oldukça ilgi çekicidir (41). MYC proteininin transkripsiyonel aktivitesi, MM'nin ileri evrelerinde artar ve düşük sağkalım ile bağlantılıdır (42). Ayrıca MYC, Gln taşıyıcılarının ekspresyonunu artırarak ve glutaminoliz inhibitörlerini baskılayarak bu süreçte önemli rol oynamaktadır (45).…”