Furthermore, the differentiation inhibited by the stretching was also restored by synthetic PPARγ ligand. Collectively, these results suggest that the inhibition of adipocyte differentiation in response to stretching is mainly attributable to the reduced expression of PPARγ2, which is mediated by activation of the ERK/MAPK system.
The development of obesity involves multiple mechanisms. Here, we identify adipocyte signaling through the guanosine triphosphatase Rho and its effector Rho-kinase as one such mechanism. Mice fed a high-fat diet (HFD) showed increased Rho-kinase activity in adipose tissue compared to mice fed a low-fat diet. Treatment with the Rho-kinase inhibitor fasudil attenuated weight gain and insulin resistance in mice on a HFD. Transgenic mice overexpressing an adipocyte-specific, dominant-negative form of RhoA (DN-RhoA TG mice) showed decreased Rho-kinase activity in adipocytes, decreased HFD-induced weight gain, and improved glucose metabolism compared to wild-type littermates. Furthermore, compared to HFD-fed wild-type littermates, DN-RhoA TG mice on a HFD showed decreased adipocyte hypertrophy, reduced macrophage recruitment to adipose tissue, and lower expression of mRNAs encoding various adipocytokines. Lipid accumulation in cultured adipocytes was associated with increased Rho-kinase activity and increased abundance of adipocytokine transcripts, which was reversed by a Rho-kinase inhibitor. Direct application of mechanical stretch to mature adipocytes increased Rho-kinase activity and stress fiber formation. Stress fiber formation, which was also observed in adipocytes from HFD-fed mice, was prevented by Rho-kinase inhibition and in DN-RhoA TG mice. Our findings indicate that lipid accumulation in adipocytes activates Rho to Rho-kinase (Rho-Rho-kinase) signaling at least in part through mechanical stretch and implicate Rho-Rho-kinase signaling in inflammatory changes in adipose tissue in obesity. Thus, inhibition of Rho-Rho-kinase signaling may provide a therapeutic strategy for disrupting a vicious cycle of adipocyte stretch, Rho-Rho-kinase signaling, and inflammation of adipose tissue that contributes to and aggravates obesity.
Whether or not inhibition of NFB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models was investigated. We compared the basal levels of phosphorylation of IB␣ and activity of NFB between cisplatin-sensitive A2780 cells and cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation of IB␣ and activity of NFB in Caov-3 cells were significantly higher than those in A2780 cells. Cisplatin caused a more marked decrease in the phosphorylation of IB␣ and activity of NFB in A2780 cells than in Caov-3 cells. Thus, high basal levels of phosphorylation of IB␣ and activation of NFB and less marked inhibition of the phosphorylation of IB␣ and activation of NFB by cisplatin seem to reduce the sensitivity of cells to cisplatin. Inhibition of NFB activity either by treatment with the IB␣ phosphorylation inhibitor (BAY 11-7085) or a specific NFB nuclear translocation inhibitor (SN-50) or by transfection of p50⌬NLS (which lacks the nuclear localization signal domain) increased the efficacy of both the cisplatin-induced attenuation of IB␣ phosphorylation and NFB activity and the cisplatininduced apoptosis. In addition, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced attenuation of both the expression of X-linked inhibitor of apoptosis protein (XIAP) and cell invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced inhibition of the intra-abdominal dissemination and production of ascites using athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that combination therapy of cisplatin with the NFB inhibitor should increase the therapeutic efficacy of cisplatin.The sensitivity of cells to chemotherapeutic drug-induced apoptosis appears to depend on the balance between proapoptotic and antiapoptotic signals. Therefore, it is possible that antiapoptotic signals such as the PI3K 1 -Akt survival cascade are involved in sensitivity to chemotherapeutic drugs. We reported that Akt inactivation sensitizes human ovarian cancer cells to cisplatin (1) and paclitaxel (2), suggesting that Akt inactivation could be a hallmark for examining the sensitivity of cells to some chemotherapeutic drugs. Possible mechanisms by which Akt promotes cell survival include phosphorylation and inactivation of the proapoptotic proteins BAD and caspase-9 (3, 4). Akt also phosphorylates and inactivates the Forkhead transcription factors, resulting in reduced expression of the cell cycle inhibitor p27 Kip1 and the Fas ligand (5-7). Via the phosphorylation of IB kinase, Akt also activates NFB, a transcription factor that has been implicated in cell survival (8,9).NFB is activated in certain cancers and in response to chemotherapy and radiation. NFB normally resides in the cytoplasm as an inactivated form in a complex with IB␣. Phosphorylation of IB␣ by upstream kinases promotes its degradation, allowing NFB to translocate to the nucleus and induce target genes (6, 7). The transcriptional activation of genes associa...
Koga and Thakkar's reoptimized (9sSp)
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