Sensitization of DNA damage–induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3σ and survivin

Abstract

Proteasome inhibition following DNA damage results in the synergistic induction of apoptosis via a nuclear factor-KBindependent mechanism. In this study, we identify the role of p53 in mediating apoptosis by the sequence-specific treatment involving the DNA-damaging, topoisomerase I -targeting drug SN-38 followed by the proteasome inhibitor PS-341 (SN-38!PS-341). The p53-dependent sensitization of DNA damage -induced apoptosis by PS-341 is accompanied by persistent inhibition of proteasome activity and increased cytosolic accumulation of p53, including higher molecular weight forms likely representing ubiquitinated species. In contrast, pretreatment with PS-341 followed by treatment with SN-38 (PS-341!SN-38), which leads to an antagonistic interaction, results in transient inhibition of proteasome activity and accumulation of significantly lower levels of p53 localized primarily to the nucleus. Whereas cells treated with PS-341!SN-38 undergo G 2 + M cell cycle arrest, cells treated with SN-38!PS-341 exhibit a decreased G 2 + M block with a concomitant increase in the sub-G 1 population. Decreased accumulation of cells in the G 2 + M phase of the cell cycle in SN-38!PS-341 -treated cells compared with PS-341!SN-38 -treated cells correlates with enhanced apoptosis and reduced expression of two p53-modulated proteins, 14-3-3S and survivin, both of which play critical roles in regulating G 2 + M progression and apoptosis. The functional role of 14-3-3S or survivin in regulating the divergent function of p53 in response to SN-38!PS-341 and PS-341!SN-38 treatment in inducing apoptosis versus G 2 + M arrest/DNA repair, respectively, was confirmed by targeted down-regulation of these proteins. These results provide insights into the mechanisms by which inhibition of proteasome activity modulates DNA damage-induced apoptosis via a p53-dependent pathway. [Mol Cancer Ther 2005;4(12):1880 -90]

Roles of Estrogen Receptor and p21Waf1 in Bortezomib-Induced Growth Inhibition in Human Breast Cancer Cells

“…These results are in agreement with previous findings in myeloid leukemia cells, melanoma, mantle lymphoma, and myeloma cells in which bortezomib activity occurs in a p53-independent manner (36)(37)(38). It has however, been reported that in some cases, bortezomib activity could occur in a p53-dependent manner, for example, in response to DNA damage (39).…”

The S-G2 phase enriched β-catenin/TCF complex ensures cell survival and cell cycle progression

“…TIAM1, a guanine nucleotide exchange factor, has been shown to enhance resistance to anoikis (apoptosis due to detachment) in SW480 colon cancer cells and thereby promotes cell survival and tumor metastasis (Minard et al, 2006). BIRC5 (commonly known as survivin) is a typical anti-apoptotic factor in colon tissues, and its increased expression positively correlates with tumor survival (Vaziri et al, 2005;Hernandez et al, 2011). Given that cells require more protection against DNA-damage-induced apoptosis during the S-G2 phase (Bartek et al, 2004;Huang et al, 2005), promoting the expression of anti-apoptotic genes during this period might present a fundamental function of Wnt-b-catenin signaling.…”

Proteasomal Dysfunction: A Common Feature of Neurodegenerative Diseases? Implications for the Environmental Origins of Neurodegeneration

“…Inhibition of the proteasome can also raise cellular p53 levels, again promoting shut-down of cell division. This is because the E3 ubiquitin ligase MDM2 targets p53 for degradation by the 26S proteasome (157).…”