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Implication of snail in metabolic stress-induced necrosis
Cho Hee Kim1, Hyun Min Jeon, Su Yeon Lee
1Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan, Korea.
Background:
Necrosis, a type of cell death accompanied by the rupture of the plasma membrane, promotes tumor progression and aggressiveness by releasing the pro-inflammatory and angiogenic cytokine high mobility group box 1. It is commonly found in the core region of solid tumors due to hypoxia and glucose depletion (GD) resulting from insufficient vascularization. Thus, metabolic stress-induced necrosis has important clinical implications for tumor development; however, its regulatory mechanisms have been poorly investigated.
Methodology/Principal Findings:
Here, we show that the transcription factor Snail, a key regulator of epithelial-mesenchymal transition, is induced in a reactive oxygen species (ROS)-dependent manner in both two-dimensional culture of cancer cells, including A549, HepG2, and MDA-MB-231, in response to GD and the inner regions of a multicellular tumor spheroid system, an in vitro model of solid tumors and of human tumors. Snail short hairpin (sh) RNA inhibited metabolic stress-induced necrosis in two-dimensional cell culture and in multicellular tumor spheroid system. Snail shRNA-mediated necrosis inhibition appeared to be linked to its ability to suppress metabolic stress-induced mitochondrial ROS production, loss of mitochondrial membrane potential, and mitochondrial permeability transition, which are the primary events that trigger necrosis.
Conclusions/Significance:
Taken together, our findings demonstrate that Snail is implicated in metabolic stress-induced necrosis, providing a new function for Snail in tumor progression.
Insights
The transcription factor Snail promotes tumor necrosis under metabolic stress. Inhibiting Snail reduces necrosis by suppressing mitochondrial reactive oxygen species (ROS) production, offering a new target for cancer progression therapies.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Necrosis, a cell death process, fuels tumor growth and aggressiveness by releasing high mobility group box 1.
- Metabolic stress, caused by hypoxia and glucose depletion, induces necrosis in solid tumors.
- Regulatory mechanisms of metabolic stress-induced necrosis are not well understood.
Purpose of the Study:
- To investigate the role of the transcription factor Snail in metabolic stress-induced necrosis.
- To elucidate the mechanisms by which Snail influences necrosis in cancer cells.
Main Methods:
- Cancer cell lines (A549, HepG2, MDA-MB-231) were cultured in 2D and as multicellular tumor spheroids.
- Cells were subjected to glucose depletion (GD) to induce metabolic stress.
- Snail expression was manipulated using short hairpin RNA (shRNA).
- Reactive oxygen species (ROS) production, mitochondrial membrane potential, and mitochondrial permeability transition were assessed.
Main Results:
- Snail was induced in a reactive oxygen species (ROS)-dependent manner in response to metabolic stress.
- Snail knockdown using shRNA inhibited necrosis in both 2D cultures and multicellular tumor spheroids.
- Snail inhibition suppressed metabolic stress-induced mitochondrial ROS production, loss of mitochondrial membrane potential, and mitochondrial permeability transition.
Conclusions:
- Snail plays a significant role in metabolic stress-induced necrosis.
- Snail's function in promoting necrosis is linked to its regulation of mitochondrial ROS production.
- These findings reveal a novel role for Snail in tumor progression and suggest it as a potential therapeutic target.
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