TY  - JOUR
A1  - Rauert-Wunderlich, Hilka
A1  - Siegmund, Daniela
A1  - Maier, Eduard
A1  - Giner, Tina
A1  - Bargou, Ralf C.
A1  - Wajant, Harald
A1  - Stühmer, Thorsten
T1  - The IKK Inhibitor Bay 11-7082 Induces Cell Death Independent from Inhibition of Activation of NF kappa B Transcription Factors
T2  - PLoS ONE
N2  - Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells.
KW  - signal inhibition
KW  - necrotic cell death
KW  - cell viability testing
KW  - cell death
KW  - small interfering RNAs
KW  - HT29 cells
KW  - phosphorylation
KW  - multiple myeloma
Y1  - 2013
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/13014
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-130140
VL  - 8
IS  - 3
ER  -