ABSTRACT: Strigolactone analogs induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells
Project description:Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Furthermore, we tested the response of patient-matched conditionally reprogrammed normal and prostate cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis compared to their normal counterpart cells. Treatment of cancer cells with strigolactone analogues was hallmarked by increased expression and activity of genes involved in stress signaling, cell cycle arrest and apoptosis. All five strigolactone analogues induced G2/M cell cycle arrest, accompanied with a decrease in the expression level of cyclin B1. Apoptosis was marked by increased percentages of cells in the sub-G1 fraction and was confirmed by Annexin V staining. In conditionally reprogramed matched tumor and normal prostate cells, the cleavage of PARP1 confirmed the specific increase in apoptosis of tumor cells. In summary, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells. There are duplicate samples for each condition. U2OS cells were treated with 2 different strigolactone analogues: ST362 or MEB55 at the concentration of 5 ppm for either 6 hr or 24 hr.Control samples were those treated with vehicle only .
Project description:Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Furthermore, we tested the response of patient-matched conditionally reprogrammed normal and prostate cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis compared to their normal counterpart cells. Treatment of cancer cells with strigolactone analogues was hallmarked by increased expression and activity of genes involved in stress signaling, cell cycle arrest and apoptosis. All five strigolactone analogues induced G2/M cell cycle arrest, accompanied with a decrease in the expression level of cyclin B1. Apoptosis was marked by increased percentages of cells in the sub-G1 fraction and was confirmed by Annexin V staining. In conditionally reprogramed matched tumor and normal prostate cells, the cleavage of PARP1 confirmed the specific increase in apoptosis of tumor cells. In summary, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.
Project description:Analogs of ManNAc, the committed precursor of sialic acid, decrease metastatic potential and trigger apoptosis in cancer cells. Adding Lev to ManNAc analogs increases their toxicity due to an ill-understood mechanism. Comparing gene expression profiles of cells treated with Ac4ManNLev and Ac4ManNAc will provide insight into the similarities and differences of these analogs. Specifically, MDA-MB-231 human breast cancer cells will be treated with Ac4ManNLev and Ac4ManNAc at doses that inhibit cell growth and induce the cell to undergo apoptosis later. RNA will be harvested in the early stage of cell arrest in order to identify genes altered by Ac4ManNLev and Ac4ManNAc.
Project description:Analogs of ManNAc, the committed precursor of sialic acid, decrease metastatic potential and trigger apoptosis in cancer cells. Adding Lev to ManNAc analogs increases their toxicity due to an ill-understood mechanism. Comparing gene expression profiles of cells treated with Ac4ManNLev and Ac4ManNAc will provide insight into the similarities and differences of these analogs. Specifically, MDA-MB-231 human breast cancer cells will be treated with Ac4ManNLev and Ac4ManNAc at doses that inhibit cell growth and induce the cell to undergo apoptosis later. RNA will be harvested in the early stage of cell arrest in order to identify genes altered by Ac4ManNLev and Ac4ManNAc. RNA preparations from three conditions, were sent to Microarray Core (E). One as control (Ethanol), and two experimental groups: high concentration Ac4ManNAc (100 uM) and high concentration Ac4ManNLev (100 uM). The aim is to gain insight into apoptosis and cell cycle arrest. Specifically, the Ac4ManNLev samples will be comprared to a less potent ManNAc analog. The RNA was amplified, labeled, and hybridized to the GLYCOv3 microarrays.
Project description:Prostate cancer is the second most occurring cancer in men worldwide, and with the advances made with screening for prostate-specific antigen, it has been prone to early diagnosis and over-treatment. To better understand the mechanisms of tumorigenesis and possible treatment responses, we developed a mathematical model of prostate cancer which considers the major signalling pathways known to be deregulated. The model includes pathways such as androgen receptor, MAPK, Wnt, NFkB, PI3K/AKT, MAPK, mTOR, SHH, the cell cycle, the epithelial-mesenchymal transition (EMT), apoptosis and DNA damage pathways. The final model accounts for 133 nodes and 449 edges. We applied a methodology to personalise this Boolean model to molecular data to reflect the heterogeneity and specific response to perturbations of cancer patients, using TCGA and GDSC datasets.
