Abstract
Here we show that bortezomib induces effective proteasome inhibition and accumulation of poly-ubiquitinated proteins in diffuse large B-cell lymphoma (DLBCL) cells. This leads to induction of endoplasmic reticulum (ER) stress as demonstrated by accumulation of the protein CHOP, as well as autophagy, as demonstrated by accumulation of LC3-II proteins. Our data suggest that recruitment of both ubiquitinated proteins and LC3-II by p62 directs ubiquitinated proteins, including I-κBα, to the autophagosome. Degradation of I-κBα results in increased NF-κB nuclear translocation and transcription activity. Since bortezomib treatment promoted I-κBα phosphorylation, ubiquitination and degradation, this suggests that the route of I-κBα degradation was not via the ubiquitin-proteasome degradation system. The autophagy inhibitor chloroquine (CQ) significantly inhibited bortezomib-induced I-κBα degradation, increased complex formation with NF-κB and reduced NF-κB nuclear translocation and DNA binding activity. Importantly, the combination of proteasome and autophagy inhibitors showed synergy in killing DLBCL cells. In summary, bortezomib-induced autophagy confers relative DLBCL cell drug resistance by eliminating I-κBα. Inhibition of both autophagy and the proteasome has great potential to kill apoptosis-resistant lymphoma cells.
Highlights
The proteasome inhibitor, bortezomib, is a novel anti-cancer drug and has been administrated successfully to treat relapsed/ refractory multiple myeloma [1,2]
In keeping with previous studies [20,21], we found that cells obtained from lymph node biopsies of previously untreated diffuse large B-cell lymphoma (DLBCL) patients were resistant to bortezomib-mediated killing
This study demonstrated that treatment of DLBCL cells with bortezomib induces autophagy which eliminates ubiquitinated I-kBa
Summary
The proteasome inhibitor, bortezomib, is a novel anti-cancer drug and has been administrated successfully to treat relapsed/ refractory multiple myeloma [1,2]. Previous studies have suggested that proteasome inhibition by bortezomib kills cancer cells via blocking inducible I-kBa degradation and subsequently NF-kB activation [3,4,5], or preventing protein degradation of proapoptotic proteins such as Bax or p53 [6,7]. It was recently reported that bortezomib-induced accumulation of polyubiquitinated proteins leads to formation of aggresomes which minimize their ‘proteotoxicity’ allowing these toxic proteins to be sequestered away from the normal cellular machinery [8,9,10]. The UPS and autophagy degradation systems are functionally coupled and linked by a multi-domain protein adapter, p62,which is able to bind ubiquitinated proteins and lead them to autophagosomes for degradation [11]. Suppression of the proteasome by bortezomib promotes autophagy in colon cancer cells [13], while inhibition of autophagy increases levels of proteasome substrates, such as p53 protein [14].The search for autophagy client proteins is important to understand how autophagy protects tumor cells from being killed
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