Abstract
Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system.
Highlights
It has been estimated that as much as one-third of all proteins are destroyed within minutes of synthesis at the ribosomes [1,2,3]
Treatment of HCT116 colon cancer cells with b-AP15 leads to a rapid accumulation of poly-ubiquitinated proteins, upregulation of Hsp70B’, and induction of programmed cell death
We previously demonstrated that untransformed cells are less sensitive to b-AP15-induced apoptosis than cancer cells such as HCT116 cells [26]
Summary
It has been estimated that as much as one-third of all proteins are destroyed within minutes of synthesis at the ribosomes [1,2,3]. The involvement of Myc and Noxa in this process has been investigated [22,23] Another potential scenario is that the accumulation of aberrant proteasomal substrates mediates the cytotoxic effects of proteasome inhibitors, either as a consequence of their inherent toxicity, or via the activation of stress signalling pathways such as the UPR [24]. Another mechanism was recently proposed whereby a fatal depletion of amino acids, due to reduced recycling of amino acids through proteasomal protein degradation, underlies proteasome inhibitorinduced cell death [25]. Our results suggest that the polyubiquitinated proteasome substrates, which accumulate upon exposure of cells to bAP15 contribute to the cytoxic effects of this drug
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