As sub strate is being translocated through the Rpt ring, the Rpn11 subunit of the 19S RP, which is positioned immedi ately above the channel through the Rpt ring, scans for ubiquitin chains. Rpn11 is a protease that removes ubiqui selleck kinase inhibitor tin chains as the substrate translocates by, which is thought to prevent the chains from clogging up the entry channel into the proteasome. Inhibition of 20S peptidase activity with bortezomib is highly cytotoxic to the plasma cell cancer multiple mye loma, and bortezomib has been an effective therapy for treating patients with this disease as well as mantle cell lymphoma. However, despite its considerable success as a therapy for MM and MCL, bor tezomib has not been approved for treating other cancers.
This is not for lack of effort over 700 bortezomib trials have or are being run, including many in indications other than MM and MCL, in attempts to identify cancers that might respond favorably. This clinical experience is consistent with in Inhibitors,Modulators,Libraries vitro data although brief exposure to proteasome inhibitors is highly cytotoxic to MM cells, it is not more cytotoxic to solid tumor cell Inhibitors,Modulators,Libraries lines than it is to non transformed cells. These data raise an obvious question why arent proteasome inhibitors more broadly effective as cancer therapeutics Inhibitors,Modulators,Libraries and pose a serious chal lenge to the generality of the proteotoxic crisis hypothesis. Most attempts to explain why proteasome inhibitors work in MM and MCL but not in other cancers have high level of constitutive NF ��B activity, might be sensitive to bortezomib.
However, this is Inhibitors,Modulators,Libraries unlikely to be the key mechanism of action, because an inhibitor of the I��B kinase IKK is not as effective as bortezomib at killing MM cells. Moreover, bortezomib does not downregu late NF ��B activity in primary MCL and MM cells or in MM xenografts. An additional explanation for the sensitivity of MM cells to bortezomib is that they exhibit a lower threshold for induction of a lethal unfolded protein response. The UPR is a homeostatic response that is mobilized by the presence of unfolded proteins in the lumen of the endoplasmic reticulum. Under normal condi tions, these unfolded proteins are retrotranslocated back to the cytosol, where they are degraded by the proteasome in a process known as ER associated degradation.
However, when the burden of unfolded proteins in the ER lumen is high, activation of the UPR enables cells to cope with this problem by inhibiting protein synthesis to reduce the load on the ER while Inhibitors,Modulators,Libraries upregulating genes to enhance the biogenic capacity of the ER. However, sustained UPR signaling can eventually commit a cell to apoptosis. Inhibition of the proteasome can sellectchem activate an apoptotic UPR in myeloma cells, presumably by inter fering with ERAD. MM plasma cells may be particularly prone to a cytotoxic UPR because of their physiological role in producing large quantities of antibody.