Proteasome Inhibitors Induce p53/p21-Independent Apoptosis in Human Glioma Cells

Abstract

The proteasome is a multiprotein complex involved in the degradation of ubiquitinated proteins. Three proteasome inhibitors, calpain inhibitor I, lactacystin and MG132, induced apoptosis in several human malignant glioma cell lines. Although proteasome inhibitors induced p53 accumulation in a cell line retaining wild-type p53 activity, p53 activity was dispensable for apoptosis since transdominant-negative p53 abrogated p53-dependent p21 induction but did not modulate apoptosis. Further, p21 was induced by higher concentrations of proteasome inhibitors in a p53-independent manner both in p53 wild-type and in p53 mutant cell lines. Although there was a strong G2/M arrest in response to proteasome inhibition in glioma cells, this G2/M arrest was also observed in p21^–/– colon carcinoma cells, suggesting that p21 is dispensable for the G2/M arrest associated with proteasome inhibition. Interestingly, the p21^–/– cells were more resistant to protease inhibitors than parental p21^+/+ cells. In summary, our data indicate that proteasome inhibition induces a p21-independent G2/M arrest and p53-independent apoptosis in human malignant glioma cells.

Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway

“…Although PIs have been shown to induce p53-independent apoptosis in glioma cells (Wagenknecht et al, 1999;Yin et al, 2005), the majority of reports suggest that PIs induce a p53-dependent form of apoptosis in most cancer cell types, such as leukemia cells (Shinohara et al, 1996;Masdehors et al, 2000), as well as melanoma and myeloma cells (Qin et al, 2005). Consistent with previous studies we observed a prominent increase of p53 levels, which was associated with transcriptional activation of the proapoptotic BH3-only gene PUMA.…”

Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM)

“…In this study, both the GBM cell lines and explants cultured with PS-341 accumulated in the G2/M phase associated with their increased levels of p21 WAF1 , p27 KIP1 , and cyclin B1. Previous studies using other proteasome inhibitors found that expression of p21 WAF1 and p27 KIP1 increased in glioma cells (Kitagawa et al, 1999;Wagenknecht et al, 1999). Furthermore, we found that levels of CDK2 and CDK4, as well as, E2F4 decreased ( Figure 4) consistent with the cells exiting the cell cycle.…”

“…In vitro screening data using a panel of 60 human tumors cell lines indicated that PS-341 has significant growth inhibitory activity against a wide variety of tumors . Other proteasome inhibitors, such as the calpain inhibitor, lactacystin, MG132, and AcLLNal, also inhibit glioma cell growth (Kitagawa et al, 1999;Wagenknecht et al, 1999;Tani et al, 2001). However, little has been reported of the effect of PS-341 on GBM cells.…”

“…The p53 protein plays an important role in cell cycle regulation and apoptosis (Kuerbitz et al, 1992;Wu and Levine, 1994). Several studies suggested that proteasome inhibitors induced apoptosis and inhibited growth of tumor cells in a p53-independent manner (Shinohara et al, 1996;Kitagawa et al, 1999;Wagenknecht et al, 1999); others have suggested these effects occurred in a p53-dependent (Lopes et al, 1997) or partly dependent fashion (Ling et al, 2003). We found that both the p53-wt and -mutant GBM cell lines and explants were sensitive to growth inhibition and apoptosis mediated by PS-341.…”

Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition

“…[7][8][9][10][11][12][13][14] On the other hand, numerous inhibitors of proteolysis induce apoptosis. [15][16][17][18][19][20][21][22][23][24] Apoptosis can be induced by a variety of stimuli, including the p53 tumor suppressor. 25 Besides wt p53, other tumor suppressors such as p27 26 and BRCA1 27 can induce apoptosis.…”