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Information × Registration Number 0217U000858, 0113U000141 , R & D reports Title The study of molecular mechanisms in response of tumor cells to the action of enzymotherapy based on starvation for arginine popup.stage_title Head Stasyk Oleh Volodymyrovych, Кандидат біологічних наук Registration Date 10-03-2017 Organization Institute of cell biology, National Academy of Sciences of Ukraine popup.description2 In the Department of Cell Signaling the research work was conducted aimed to decipher molecular markers of tumor cells sensitivity to arginine deprivation and development of efficient metabolic anticancer modalities based on arginine-degrading enzymes. In particular, human glioma cells with gene knockdown of argininosuccinate synthetase (ASS) were obtained and studied. It was shown that inhibition of ASS gene expression correlate inversely with increased metastatic potential, including the increase in migration and clonogenic potential. We revealed that arginine withdrawal selectively leads to decrease in mobility and invasiveness of human tumor cells of different types. The reason for such an effect on the cell motility is reduction of polymerized fractions of actin microfilaments, while limitation of the invasion correlates with decreased levels of matrix metalloproteinases, which are necessary for the destruction of the extracellular matrix. The combination of arginine deprivation and sodium nitroprusside, the donor of nitrogen (II) oxide, is accompanied by the additional depolymerization of actin cytoskeleton and leads to intensification of the antineoplastic potential of arginine deficit. It was shown for the first time that arginine deficiency induced the endoplasmic reticulum stress in solid human tumor cells, in accordance with the increased gene expression of chaperones of ER and activation of two out of three sensors of ER stress. Regulation of translation of starved epithelial tumor cells occurs via the mTORC1- and GCN2/eIF2?-dependent signaling pathways. It was established that the loss of the ability of tumor cells to arrest cell cycle in phase G1/G0 under arginine depletion may be one of the reasons for their increased sensitivity to arginine deficiency in monolayer cell culture. For colon cancer cells, it was show that the regulation of translation by mTORC1- and GCN2/eIF2?- dependent signaling pathways under arginine starvation determines the differential sensitivity to amino acid deficiency between the studied tumor cell lines, as well as between monolayer and spheroid cultures of each particular cell line, respectively. We revealed that not only induction of ASS gene expression, but also the concentration of extracellular citrulline determined the growth and survival of tumor cells in a arginine-free medium. It was found that low doses of the arginine analog canavanine significantly enhance the endoplasmic reticulum stress under arginine depleted conditions and lead to increase of the cytotoxic potential of the proposed treatment combination. Probably the canavanine inhibits the induction of gene expression ASS and inhibits the ability of tumor cells to utilize the citrulline for arginine synthesis. It was shown that the combination of arginine deficiency with low doses of canavanine significantly increases the radiosensitivity of human tumor cells regardless of the extracellular citrulline concentration. Product Description popup.authors Ігуменцева Н.І. Барська М.Л. Бобак Я.П. Винницька-Мироновська Б.О. Вовк О.І. Воробець З.Д. Данилейченко В.В. Карацай О.В. Курліщук Ю.В. Линів Л.С. Маєвська О.М. Перевєрзєва Г.Г. Ржепецький Ю.А. Сенчук О.Ю. Сибірна Н.О. Стасик О.Г. Чень О.І. Чернишук С.В. Шуваєва Г.Ю. popup.nrat_date 2020-04-02 Close