Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.
We have previously described a functional model for identification of human liver tumor suppressor genes in which human chromosome 11 was introduced into rat liver epithelial tumor cell lines via microcell-mediated chromosome transfer, producing microcell hybrid (MCH) cell lines that exhibit suppression of tumorigenicity in vivo. Chromosome deletion mapping studies identified a 950-kb region of 11p11.2-p12 that was retained in all suppressed MCH cell lines, suggesting that this region may harbor one or more genes with liver tumor suppressor function. In this study, we generated a comprehensive transcription map of the 11p11.2-p12 liver tumor suppressor region through examination of 142 expressed sequence tag (EST) markers among a group of suppressed MCH cell lines. Of 142 ESTs examined, 19 were localized within the 11p11.2-p12 liver tumor suppressor region. RT-PCR analysis of gene expression for these 19 ESTs among an index panel of suppressed MCH cell lines (n = 3) identified 11 potential candidate liver tumor suppressor genes. Examination of candidate gene expression among six additional suppressed MCH cell lines reduced the number of potential candidate genes to three (stSG30184, stSG10014, and stSG29748). Northern blot analysis of suppressed MCH cell lines and derived tumor cell lines suggested stSG30184 as the best candidate liver tumor suppressor gene. The 3.7 kb stSG30184 transcript was expressed by all suppressed MCH cell lines, but expression was extinguished coordinately with reexpression of tumorigenicity by these cells, consistent with a tumor suppressor gene. Subsequent characterization of this EST indicates that it is a novel transcript with expression in a broad range of tissue types. Further characterization of the genes identified in this study will provide a greater understanding of their role in the molecular pathogenesis of neoplastic liver disease.
This article documents an experimental study conducted to examine the tensile and shear strength behaviour of uniform sands cemented artificially by heat treatment of added polyethylene fines. The results show that, like other cemented sands, the strength of polymer-bonded sands (PBS) is dependent on cement content, grain size and mineralogy, yet the tensile and shear strengths of PBS are significantly larger than those of other artificially cemented sands. Microscopy observations reveal that the strength of the bond shared by the polymer and the mineral surface gives rise to the cementation strength. Acoustic emissions complement the shear strength data by confirming the transition between a cementation-controlled regime at low confinement and a friction-controlled regime at high confinement.
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