Abstract
Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms.
Highlights
Intracellular protein metabolism involves both synthesis as well as degradation of proteins
The vast majority of proteins is selectively degraded by the ubiquitin-proteasome system (UPS)
Growing awareness of the pivotal role of the UPS in normal cell physiology as well as in disease propelled the development of proteasome inhibitors for therapeutic applications [2,3,4]
Summary
Intracellular protein metabolism involves both synthesis as well as degradation of proteins. Overexpression of Bcl-2 did not alter the basal proteasome activity nor its inhibition induced by bortezomib [15] These observations confirmed a differential proteasomal phenotype comparing H460 and SW1573 cells and indicate that the proteasomal phenotype is independent of the apoptotic phenotype. To examine the possibility that apoptotic factors might explain the differential sensitivity for apoptosis induction once the proteasome has been effectively inhibited, we assessed the expression of heat shock proteins, such as Hsp, Hsp and Hsp upon exposure of H460 and SW1573 cells to bortezomib. A low IC50(e.g. SW1573 cells), as determined by MTT assay, does not necessarily correspond to enhanced apoptosis induction in a certain cell line, compared to a cell line with a higher IC50 (e.g., H460 cells)
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