Abstract
BackgroundThe proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL). However, NF-κB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-κB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear.ResultsProteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-κB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA). Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231) and a breast carcinoma cell line (MDA-MB-468), the bortezomib-resistant NF-κB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10) displayed bortezomib-resistant constitutive NF-κB activity.ConclusionOur findings show that bortezomib-resistant NF-κB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.
Highlights
The proteasome inhibitor bortezomib can inhibit activation of the transcription factor nuclear factor κB (NF-κB), a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL)
To avoid complications arising from the latent membrane protein 1 of EBV, which has been shown to activate NF-κB [66], we first investigated constitutive NFκB complexes in the EBV-negative MCL cell lines, Jeko-1 and Rec-1, using Electrophoretic mobility shift assay (EMSA)
NF-κB p50/p65 and p50/cRel heterodimers can be activated via both canonical, PIR, and other pathways [34,44,45], suggesting that distinct mechanisms mediating constitutive NF-κB activation may exist in these MCL cell lines
Summary
The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL). While MCL cells have been shown to harbor constitutive NFκB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear. The need for new treatment strategies has led to the development of a novel class of pharmacologic agents, the proteasome inhibitors. After demonstrating activity in patients with refractory multiple myeloma with a manageable toxicity profile, bortezomib (Velcade; Millenium Pharmaceuticals Inc, Cambridge, MA), a reversible inhibitor of chymotryptic-like activity in the 26S proteasome, was the first agent of this class to be approved for clinical use [16,17,18,19,20]. The efficacy of bortezomib in treating previously refractory cases of MCL is believed to involve multiple signaling pathways, and among them, the nuclear factor κB (NF-κB) pathways [25,26,27]
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