p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells

Abstract

We have examined the effects of inhibition of the 26S proteasome in a murine mammary cell line, KIM-2 cells using the peptide aldehyde inhibitor MG132. These studies have demonstrated a clear requirement for proteasome function in cell viability. Induction of apoptosis was observed following MG132 treatment in KIM-2 cells and this death was shown to be dependent on the cell actively traversing the cell cycle. KIM-2 cells were generated using a temperature sensitive T-antigen (Tag) and studies at the permissive temperature (338C) have shown that a Tag binding protein was essential for this apoptotic response. Studies in two additional cell lines, HC11, which is a mammary epithelial cell line carrying mutant p53 alleles and p53 null ES cells suggest that p53 is actively required for the apoptosis induced as a consequence of proteasome inhibition. These results suggest a pivotal role for the 26S proteasome degradation pathway in progression through the cell cycle in proliferating cells. Cell Death and Differentiation (2001) 8, 210 ± 218.

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

“…The p53 and estrogen receptor status were not recorded but may be of interest in future trials, as in vitro studies suggest proteasome inhibition is at least partially dependent on the p53 status in breast cancer (MacLaren et al, 2001), and Figure 1 Mean change from baseline in alpha-1 acid glycoprotein concentrations by bortezomib dose level during the study. The number of patients available for each analysis are shown above or below each column; notably, the significant decrease from baseline seen at cycle 6, day 1, in the bortezomib 1.5 mg m À2 group arises from evaluation of data from only one patient.…”

Regulation of apoptosis by the ubiquitin and proteasome pathway

“…Proteasome inhibition induces usually p53 accumulation within cells, which may be resposible for the induction of apoptosis in the case of proliferating cells with normal p53 [93]. However, there are numerous examples, that proteasome inhibitors induce apoptosis in cells lacking a functional p53 [94,95,96].…”

BCL-2 family regulation by the 20S proteasome inhibitor bortezomib

“…This is despite inhibiting the 20S proteasome in healthy cells, suggesting differential susceptibility of malignant compared with normal cells to proteasome inhibition LeBlanc et al, 2002). The immediate downstream consequences of inhibiting the 20S activity are complex and are dependent on the phenotype, for example, p53 expression MacLaren et al, 2001). G 2 -M arrest is correlated with elevation of the cyclin-dependent kinase inhibitors p21, p27, p16, p18 and p19 Ling et al, 2003a;Coquelle et al, 2006).…”