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BackgroundThe p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage.ResultsWe identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53.ConclusionsOur findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.

Combining microtubule-targeting anti-mitotic drugs with targeted apoptosis potentiators is a promising new chemotherapeutic strategy to treat cancer. In this study we investigate the cellular mechanism by which Navitoclax (previously called ABT-263), a Bcl-2 family inhibitor, potentiates apoptosis triggered by paclitaxel and an inhibitor of Kinesin-5 (KSP), across a panel of epithelial cancer lines. Using time-lapse microscopy, we show that Navitoclax has little effect on cell death during interphase, but strongly accelerates apoptosis during mitotic arrest, and greatly increases the fraction of apoptosis-resistant cells that die. By systematically knocking down individual Bcl-2 proteins we determined that Mcl-1 and Bcl-xL are the primary negative regulators of apoptosis during prolonged mitotic arrest. Mcl-1 levels decrease during mitotic arrest due to an imbalance between synthesis and turnover, and turnover depends in part on the MULE/HUWE1 E3 ligase. The combination of Mcl-1 loss with inhibition of Bcl-xL by Navitoclax causes rapid apoptosis in all lines tested. Variation in expression levels of Mcl-1 and Bcl-xL largely determine variation in response to anti-mitotics alone, and anti-mitotics combined with Navitoclax, across our panel. We conclude that Bcl-xL is a critical target of Bcl-2 family inhibitors for enhancing the lethality of anti-mitotic drugs in epithelial cancers, and combination treatment with Navitoclax and a spindle specific anti-mitotic, such as a Kinesin-5 inhibitor, might be more effective than paclitaxel alone.

Background and ObjectiveThe impact of perioperative allogenenic blood transfusion (ABT) on clinical outcomes for hepatocellular carcinoma (HCC) is conflicting and unclear. The aim of this meta-analysis is to evaluate the association between ABT and HCC clinical outcomes. Outcomes evaluated were all-cause death, tumor recurrence and postoperative complications.MethodsRelevant articles were identified through MEDLINE search (up to November 2012). Meta-analyses were performed by using the fixed or random effect models. Study heterogeneity was assessed by Q-test and I2 test. Publication bias was evaluated by funnel plots, Egger′s and Begg’s test.ResultsA total of 5635 cases from 22 studies finally met our inclusion criteria. Meta-analysis indicated HCC patients with ABT had an increased risk of all-cause death at 3 and 5 years after surgery (respectively: OR = 1.92, 95% CI, 1.61–2.29,P<0.001; OR = 1.60, 95% CI, 1.47–1.73,P<0.001 ) compared with those without ABT. The risk of tumor recurrence was significantly higher for ABT cases at 1, 3 and 5 years (respectively: OR = 1.70, 95% CI, 1.38–2.10, P<0.001; OR = 1.22, 95% CI, 1.08–1.38, P<0.001; OR = 1.16, 95% CI, 1.08–1.24, P<0.001). The HCC cases with ABT significantly increased postoperative complications occurrence compared with non-ABT cases (OR = 1.78,95% CI, 1.34–2.37, P<0.001).ConclusionsThe findings from the current meta-analysis demonstrated that ABT was associated with adverse clinical outcomes for HCC patients undergoing surgery, including increased death, recurrence and complications. Therefore, ABT should not be performed if possible.