TY  - JOUR
A1  - Effenberger, Madlen
A1  - Bommert, Kathryn S.
A1  - Kunz, Viktoria
A1  - Kruk, Jessica
A1  - Leich, Ellen
A1  - Rudelius, Martina
A1  - Bargou, Ralf
A1  - Bommert, Kurt
T1  - Glutaminase inhibition in multiple myeloma induces apoptosis via MYC degradation
JF  - Oncotarget
N2  - 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.
KW  - Multiple Myeloma
KW  - glutaminase inhibition
KW  - apoptosis
KW  - MYC
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170168
VL  - 8
IS  - 49
ER  - 
TY  - JOUR
A1  - Haertle, Larissa
A1  - Buenache, Natalia
A1  - Cuesta Hernández, Hipólito Nicolás
A1  - Simicek, Michal
A1  - Snaurova, Renata
A1  - Rapado, Inmaculada
A1  - Martinez, Nerea
A1  - López-Muñoz, Nieves
A1  - Sánchez-Pina, José María
A1  - Munawar, Umair
A1  - Han, Seungbin
A1  - Ruiz-Heredia, Yanira
A1  - Colmenares, Rafael
A1  - Gallardo, Miguel
A1  - Sanchez-Beato, Margarita
A1  - Piris, Miguel Angel
A1  - Samur, Mehmet Kemal
A1  - Munshi, Nikhil C.
A1  - Ayala, Rosa
A1  - Kortüm, Klaus Martin
A1  - Barrio, Santiago
A1  - Martínez-López, Joaquín
T1  - Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma
JF  - Cancers
N2  - For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.
KW  - Multiple Myeloma
KW  - drug resistance
KW  - proteasome inhibitors
KW  - immunoglobulin rearrangement
KW  - ATPase activity
KW  - PSMC2
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305013
SN  - 2072-6694
VL  - 15
IS  - 2
ER  -