The ⑀4 genotype of apolipoprotein E (apoE4) is the most established predisposing factor in Alzheimer's disease (AD); however, it remains unclear how apoE4 contributes to the pathophysiology. Here, we report that the apoE4 protein (ApoE4) evokes apoptosis in neuronal cells through the low-density lipoprotein receptor-related protein (LRP) and heterotrimeric GTPases. We examined neuron/neuroblastoma hybrid F11 cells and found that these cells were killed by 30 g/ml ApoE4, but not by 30 g/ml ApoE3. ApoE4-induced death occurred with typical features for apoptosis in time-and dose-dependent manners, and was observed in SH-SY5Y neuroblastomas, but not in glioblastomas or non-neuronal Chinese hamster ovary cells. Activated, but not native, ␣2-macroglobulin suppressed this ApoE4 toxicity. Suppression by the antisense oligonucleotide to LRP and inhibition by low nanomolar concentrations of LRP-associated protein RAP provided evidence for the involvement of LRP. The involvement of heterotrimeric GTPases was demonstrated by the findings that (1) ApoE4-induced death was suppressed by pertussis toxin (PTX), but not by heat-inactivated PTX; and (2) transfection with PTX-resistant mutant cDNAs of G␣ i restored the toxicity of ApoE4 restricted by PTX. We thus conclude that one of the neurotoxic mechanisms triggered by ApoE4 is to activate a cell type-specific apoptogenic program involving LRP and the G i class of GTPases and that the apoE4 gene may play a direct role in the pathogenesis of AD and other forms of dementia.
XRCC2 has been shown to increase the radioresistance of some cancers. Here, XRCC2 expression was investigated as a predictor of preoperative radiotherapy (PRT) treatment response in locally advanced rectal cancer (LARC). XRCC2 was found to be overexpressed in rectal cancer tissues resected from patients who underwent surgery without PRT. In addition, overall survival for LARC patients was improved in XRCC2-negative patients compared with XRCC2-positive patients after treatment with PRT (P < 0.001). XRCC2 expression was also associated with an increase in LARC radioresistance. Conversely, XRCC2-deficient cancer cells were more sensitive to irradiation in vitro, and a higher proportion of these cells underwent cell death induced by G2/M phase arrest and apoptosis. When XRCC2 was knocked down, the repair of DNA double-strand breaks caused by irradiation was impaired. Therefore, XRCC2 may increases LARC radioresistance by repairing DNA double-strand breaks and preventing cancer cell apoptosis. Moreover, the present data suggest that XRCC2 is a useful predictive biomarker of PRT treatment response in LARC patients. Thus, inhibition of XRCC2 expression or activity represents a potential therapeutic strategy for improving PRT response in LARC patients.
Long noncoding RNA (lncRNA) maternally expressed 3 (MEG3) has been implicated as a tumor suppressor gene in several human cancer types. However, little is known regarding its involvement and potential mechanism in human breast cancer. In this study, we explored the effect of MEG3 on the growth of human breast cancer cell line MDA‐MB‐231 in vitro and in vivo, and sought to elucidate the potential signaling mechanisms. Ectopic overexpression of MEG3 using a lentiviral vector Lv‐MEG3 significantly inhibited breast cancer cell growth in vitro and a cancer xenograft growth in vivo. MEG3 overexpression led to marked increase of apoptosis in breast cancer cells as determined using flow cytometry and fragmented DNA labeling. Moreover, ectopic expression of MEG3 increased the expression of endoplasmic reticulum (ER) stress–related proteins required for unfolded protein response, including glucose‐regulated protein 78 (GRP78), inositol‐requiring enzyme 1 (IRE1), protein kinase RNA (PKR)‐like ER kinase (PERK), and activated transcription factor 6 (ATF6), as well as proapoptotic proteins CCAAT/enhancer binding protein homologous protein (CHOP) and caspase‐3. Finally, MEG3 overexpression markedly increased nuclear factor κB (NF‐κB) expression, NF‐κB translocation to the nucleus, and p53 expression, whereas pharmacological inhibition of NF‐κB completely abolished MEG3‐induced activation of p53. Together, these results suggest that MEG3 inhibits breast cancer growth and induces breast cancer apoptosis, partially via the activation of the ER stress, NF‐κB and p53 pathways, and that NF‐κB signaling is required for MEG3‐induced p53 activation in breast cancer cells. Our results indicate targeting lncRNA MEG3 may represent a novel strategy for breast cancer therapy.
The effect of FK506, a potent immunosuppressive agent, on 7,12-dimethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13- acetate (TPA)-promoted skin papilloma formation was examined in CD-1 mice. A topical application of FK506 to mouse skin 15 min before each TPA treatment resulted in a dose-related inhibition of tumor formation. FK506 (1 mumol) almost completely inhibited tumor formation. This inhibitory effect of FK506 was not due to any damage inflicted on the initiated cells but due to its anti-tumor-promoting action. A topical application of FK506 also inhibited epidermal ornithine decarboxylase induction and skin inflammation caused by TPA in a dose-related manner. Significant inhibition by FK506 of TPA-induced endogenous protein phosphorylation in intact epidermal cells was not detected. These results indicate that FK506 inhibits TPA-induced tumor promotion at a step distal to the endogenous protein phosphorylation by TPA.
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