Registration Number
0217U000856,
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
The study of the impact of arginine starvation on cell cycle regulation in cells with different sensitivity to deficiency of this amino acid was conducted in our department. It was revealed that arginine lacking led to dephosphorylation of protein Rb in human colon cancer NBT-116 and HT29 cells with an arrest in G1-S transition of the cell cycle. The use of flow cytometry allowed showing the loss of ability to arrest of tumor cells in G0 / G1 phase of cell cycle may be one from the reason for their increased sensitivity to arginine deficiency in the medium. The role of MAPK signaling in tumor cell response on arginine deficiency was investigated. Human glioblastoma cell lines U251MG under arginine starvation displayed the activation of stress-activated protein kinase (ASK1, SAPK / JNK, p38 MAPK) and deactivation of pro-proliferative ERK 1/2 kinase. HCT-116 and HT29cells under such conditions were characterized by the activation of two MAPK - ERK1 / 2 and p38 / MAPK. No distinct correlation was found between the sensitivity of cells to arginine deficiency and dynamics of MAPK activation. We have shown for the first time that as response on arginine starvation epithelial tumor cells induced the expression of markers of endoplasmic reticulum stress (ER) such as GRP78, GRP94, CHOP and EDEM and activated the signaling pathways IRE1?-XBP1s and ATF6. Arginine deficiency induces gene expression of the signaling pathway GCN2 / eIF2? / ATF4, which leads to a total stop of translation. Blocking translation also occurs due to inactivation of mTORC1 signaling pathway in cells HCT-116 and U251 but not in HT29 cell line, which is sensitive to arginine deficiency. Consequently, arginine deprivation induces metabolic stress leading to abnormality of the cell cycle regulation and protein synthesis in tumor cells. Inability of tumor cells to activate the adaptive response can be a major mechanism of hypersensitivity of certain tumor cells to arginine deficiency.
Product Description
popup.authors
Ігуменцева Н.І.
Барська М.Л.
Бобак Я.П.
Вовк О.І.
Воробець З.Д.
Данилейченко В.В.
Денега І.О.
Карацай О.В.
Курліщук Ю.В.
Линів Л.С.
Маєвська О.М.
Переверзєва Г.Г.
Ржепецький Ю.А.
Сенчук О.Ю.
Сибірна Н.О.
Стасик О.Г.
Чень О.І.
Чернишук С.В.
popup.nrat_date
2020-04-02
