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SummaryOncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer.

Abstract-Maternal obesity in rodents is associated with increased adiposity, impaired glucose tolerance, and hypertension in adult offspring. In this study we investigated the influence of maternal obesity in the rat on blood pressure and blood pressure regulatory pathways in juvenile and adult offspring. Obesity was induced before pregnancy in female Sprague-Dawley rats by feeding a highly palatable energy-dense diet. In juvenile animals (30 days of age), before the onset of obesity and hyperleptinemia, basal nighttime mean arterial pressure was significantly raised in the offspring of obese dams (OffOb) relative to offspring of controls (OffCon; mean arterial pressure, males: OffOb, 121.8Ϯ0.6 mm Hg versus OffCon, 115.0Ϯ0.5 mm Hg, nϭ6, PϽ0.01; females: OffOb, 125.4Ϯ0.4 mm Hg versus OffCon, 114.4Ϯ0.5 mm Hg, nϭ6, PϽ0.001), as was the mean arterial pressure response to restraint stress (PϽ0.01). The pressor response to a leptin challenge was enhanced in OffOb rats (⌬mean arterial pressure: OffOb, 9.7Ϯ0.8 mm Hg versus OffCon, 5.3Ϯ1.3 mm Hg; nϭ8; PϽ0.05). Renal tissue norepinephrine content (PϽ0.001) and renin expression (PϽ0.05) were markedly raised. Analysis of heart rate variability revealed an increased low:high frequency ratio in OffOb versus OffCon rats (PϽ0.05). At 90 days, hypertension in OffOb rats persisted and was abolished by ␣1-and ␤-adrenergic blockade, and cardiovascular responses to phenylephrine or sodium nitroprusside indicated altered baroreceptor function. The exaggerated pressor response to leptin in OffOb rats was maintained. Hypertension in the offspring of obese rats may arise from persistent sympathoexcitatory hyperresponsiveness acquired in early stages of development. (Hypertension. 2010;55:76-82.)Key Words: hypertension Ⅲ sympathetic activity Ⅲ leptin Ⅲ developmental programming Ⅲ kidney T he influences of the worldwide obesity epidemic on reproductive health in women, particularly in relation to an adverse pregnancy outcome, present a significant health burden and a substantive healthcare cost. 1 We now appreciate that consequences for the child may extend well beyond the perinatal period. Evidence from observational cohort studies has suggested that maternal obesity is an independent determinant of childhood obesity and metabolic syndrome, arising from adverse influences of the maternal "hypernutritional" environment on the developing child; however, because of a multiplicity of confounding variables, causality cannot easily be proven. 2-5 Studies on experimental animals have provided the strongest evidence for a causal relationship. 2,6 -8 We have developed a rodent model of maternal obesity in mice 9 and rats 6 and have shown that adult offspring display many features of the metabolic syndrome, including hypertension at 3 months of age. 9 We reported recently that hyperphagia and increased adiposity in adult rat offspring are associated with resistance to the anorectic and weight-reducing actions of leptin, as well as impaired leptin signaling in the arcuate nucleus of the hypothala...