In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.

PurposeFTY720, known as fingolimod, is a new immunosuppressive agent with effective anticancer properties. Although it was recently confirmed that FTY720 inhibits cancer cell proliferation, FTY720 can also induce protective autophagy and reduce cytotoxicity. Blocking autophagy with Beclin 1 siRNA after treatment with FTY720 promotes apoptosis. The objective of this study was to enhance the anticancer effect of FTY720 in hepatocellular carcinoma (HCC) by targeted co-delivery of FTY720 and Beclin 1 siRNA using calcium phosphate (CaP) nanoparticles (NPs).Materials and methodsFirst, the siRNA was encapsulated within the CaP core. To form an asymmetric lipid bilayer structure, we then used an anionic lipid for the inner leaflet and a cationic lipid for the outer leaflet; after removing chloroform by rotary evaporation, these lipids were dispersed in a saline solution with FTY720. The NPs were analyzed by transmission electron microscopy, dynamic light scattering and ultraviolet–visible spectrophotometry. Cancer cell viability and cell death were analyzed by MTT assays, fluorescence-activated cell sorting analysis and Western blotting. In addition, the in vivo effects of the NPs were investigated using an athymic nude mouse subcutaneous transplantation tumor model.ResultsWhen the CaP NPs, called LCP-II NPs, were loaded with FTY720 and siRNA, they exhibited the expected size and were internalized by cells. These NPs were stable in systemic circulation. Furthermore, co-delivery of FTY720 and Beclin 1 siRNA significantly increased cytotoxicity in vitro and in vivo compared with that caused by treatment with the free drug alone.ConclusionThe CaP NP system can be further developed for co-delivery of FTY720 and Beclin 1 siRNA to treat HCC, enhancing the anticancer efficacy of FTY720. Our findings provide a new insight into HCC treatment with co-delivered small molecules and siRNA, and these results can be readily translated into cancer clinical trials.

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To analyze refreezing state and permafrost table of the frozen ground for the Qinghai-Tibet DC Transmission Line Engineering, temperature monitoring tests of fine-grained frozen soil were carried out and the thawing depth of backfilled soil was measured in Wudaoliang region of the Tibetan Plateau. The ground temperature fluctuates over time, and the fluctuation characteristics are determined by soil properties, climate, depth and other factors. The seasonally thawed layer is in the shallow of undisturbed frozen ground and backfilled soil. The maximum thawing depth of backfilled soil was about 2.3m more than permafrost table of the undisturbed frozen ground. Soil near the foundation slab was keeping frozen state. The results show that the construction of frozen ground in cold season is helpful to refreeze and keep frozen state of the ground, and can provide a basis for stability analysis of the engineering foundation.

By theory analysis and field tests, failure model of soil around foundation and ultimate uplift resistance of enlarged bass shallow foundation were analyzed. The results showed that the deformation and failure process of soil around foundation under uplift load undergone three phases: 1) soil upon enlarged base compressed, 2) appearance and extension of plastic zone of soil around foundation, and 3) soil around foundation general shear failure. With the combination of the Limit Equilibrium Method, and Sliding Curve Theory, a simplified theory model to calculate net ultimate uplift resistance of shallow foundation assuming cir failure surface under uplift load was established. Then three examples were calculated by this method and the good agreement between theory calculation solution and experimental results validated the rationality of the model. The study in this paper provided an important theoretical support and brand-new idea on calculation method of uplift capacity of foundation with enlarged base and failure surface characteristics determination of soil around foundation.