TRIP-Br1 oncoprotein inhibits autophagy, apoptosis, and necroptosis under nutrient/serum-deprived condition
Samil Jung1, Chengping Li1, Jingjing Duan1
1Department of Life Systems, Sookmyung Women's University, Seoul, 140-742, South Korea.
Abstract:
TRIP-Br1 oncogenic protein has been shown to have multiple biological functions in cells. In this study, we demonstrate that TRIP-Br1 functions as an oncoprotein by inhibiting autophagy, apoptosis, and necroptosis of cancer cells and eventually helping them to survive under the nutrient/serum starved condition. TRIP-Br1 expression level was significantly increased in conditions with low levels of nutrients. Nutrient depleted conditions were induced by culturing cancer cells until they were overcrowded with high cell density or in media deprived of glucose, amino acids, or serum. Among them, serum starvation significantly enhanced the expression of TRIP-Br1 only in all tested breast cancer cell lines (MCF7, MDA-MB-231, T47D, MDA-MB-435, Hs578D, BT549, and MDA-MB-435) but not in the three normal cell lines (MCF10A, HfCH8, and NIH3T3). As compared with the control cells, the introduction of TRIP-Br1 silencing siRNA into MCF7 and MDA-MB-231 cells accelerated cell death by inducing apoptosis and necroptosis. In this process, TRIP-Br1 confers resistance to serum starvation-induced cell deaths by stabilizing the XIAP protein and inhibiting cellular ROS production. Moreover, our data also show that the intracellular increase of TRIP-Br1 protein resulting from serum starvation seems to occur in part through the blockage of PI3K/AKT signaling pathway.
Insights
The TRIP-Br1 oncoprotein promotes cancer cell survival by blocking cell death pathways like apoptosis and necroptosis, especially under nutrient-deprived conditions. Its elevated expression in breast cancer cells helps them resist serum starvation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- TRIP-Br1 is an oncogenic protein with diverse cellular functions.
- Cancer cells require mechanisms to survive stressful conditions like nutrient deprivation.
Purpose of the Study:
- To investigate the role of TRIP-Br1 in cancer cell survival under nutrient/serum starvation.
- To elucidate the molecular mechanisms by which TRIP-Br1 promotes cancer cell resistance.
Main Methods:
- Culturing breast cancer cell lines (MCF7, MDA-MB-231, etc.) under nutrient-depleted conditions (serum starvation, glucose/amino acid deprivation).
- Utilizing TRIP-Br1 silencing siRNA to assess its impact on cell death.
- Measuring XIAP protein levels and cellular ROS production.
- Analyzing the involvement of the PI3K/AKT signaling pathway.
Main Results:
- TRIP-Br1 expression significantly increased in cancer cells under nutrient/serum starvation but not in normal cells.
- TRIP-Br1 silencing accelerated apoptosis and necroptosis in breast cancer cells.
- TRIP-Br1 confers resistance to serum starvation by stabilizing XIAP and inhibiting ROS production.
- Serum starvation-induced TRIP-Br1 increase involves partial blockage of the PI3K/AKT pathway.
Conclusions:
- TRIP-Br1 acts as an oncoprotein by inhibiting autophagy, apoptosis, and necroptosis, enhancing cancer cell survival during nutrient/serum starvation.
- TRIP-Br1's protective role involves XIAP stabilization and ROS inhibition, potentially mediated by the PI3K/AKT pathway.
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