Project description:A major contributor to cancer mortality is recurrence and subsequent metastatic transformation following therapeutic intervention. In order to develop new treatment modalities or improve the efficacy of current ones it is important to understand the molecular mechanisms that promote therapy-resistance to cancer cells. One pathway that has been demonstrated to therapy resistance is autophagy, a self-digestive process that can eliminate unnecessary or damaged organelles to protect cancer cells from necrosis. Effective targeting of this pathway could lead to the development of new therapies. In our studies, we found that the VEGF-C/NRP-2 axis is involved in the activation of autophagy, which is essential for the survival of cancer cells following chemotherapy treatment. Furthermore, we identified two VEGF-C/NRP-2-regulated genes, LAMP-2 and WDFY-1 that have previously been suggested to participate in autophagy and vesicular trafficking. The upregulation of WDFY-1 upon depleted level of VEGF-C contributed to cytotoxic drug-mediated cell death. Altogether, these data suggest a link between VEGF-C/neuropilin-2 axis and cancer cell survival despite the presence of chemotherapy-induced stress. Human prostate cancer cell lines PC3, Du145 and pancreatic cancer cell line CaPan1 were cultured at 37οC either in RPMI 1640 with L-glutamine or in DMEM media with 10% fetal bovine serum and supplemented with penicillin/streptomycin. PC3 stable transfected cell line was growing in presence of 1µg/ml puromycin selection pressure. Cells were transfected with SmartPool cocktail siRNA for NRP-2, VEGF-C, LAMP-2, and WDFY-1, using DharmaFECT 1-4. siRNA transfection was allowed to proceed 72 h before collection of whole-cell extract or total RNA.To identify potential pathways involved in this VEGF-C-mediated cell survival, we performed a microarray study comparing cells depleted in either VEGF-C or NRP-2 using SmartPool siRNA to PC-3 cells treated with scrambled siRNA. Upon comparison of the two data sets, we found 34 gene-tags that were commonly up- or down-regulated in both NRP-2- and VEGF-C-depleted cells.

Dataset Information

Regulation of telomere silencing by the core histones-autophagy-Sir2 axis.

Publications

Regulation of telomere silencing by the core histones-autophagy-Sir2 axis.

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