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Metallothionein is a potential negative regulator of apoptosis
Ryuya Shimoda1, William E Achanzar, Wei Qu
1National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Abstract:
Apoptotic resistance can either be desirable or undesirable, depending on the conditions. In cancer chemotherapy, it is critical that tumor cells are selectively and effectively killed while leaving normal cells undamaged. Since acquisition of apoptotic resistance appears to be a common occurrence during malignant transformation, elucidating the mechanisms underlying apoptotic resistance is an area of intense study. Previous studies have revealed that metallothionein (MT) can protect cells from apoptosis induced by oxidative stress and metals. In the present study, we tested the hypothesis that the presence of MT may somehow modulate apoptosis. Our results revealed a strong linear negative correlation between basal MT levels and etoposide-induced apoptosis in the human tumor cell lines PLC/PRF/5, H460, and HepG2 (r = -0.991). In HepG2 cells, 24 h pretreatment with cadmium resulted in concentration-dependent increases in MT levels and marked decreases in etoposide-induced apoptosis. Zinc pretreatment also resulted in increased MT synthesis and decreased etoposide-induced apoptosis. More importantly, induced MT levels were negatively correlated with sensitivity to etoposide-induced apoptosis (r = -0.965). These suggest that MT may play a role in regulating apoptosis and that modulating MT expression may provide a strategy for altering cellular resistance to chemotherapeutic compounds.
Insights
Metallothionein (MT) presence correlates with reduced cancer cell apoptosis. Modulating MT levels could alter cellular resistance to chemotherapy, offering a potential strategy for cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- Apoptotic resistance is a key factor in cancer chemotherapy, impacting treatment efficacy.
- Metallothionein (MT) is known to protect cells from oxidative stress and metal-induced apoptosis.
- Understanding mechanisms of apoptotic resistance is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the hypothesis that metallothionein (MT) modulates apoptosis.
- To determine the correlation between MT levels and etoposide-induced apoptosis in human tumor cell lines.
Main Methods:
- Analysis of basal MT levels and etoposide-induced apoptosis in PLC/PRF/5, H460, and HepG2 cell lines.
- Pretreatment of HepG2 cells with cadmium and zinc to induce MT synthesis.
- Correlation analysis to quantify the relationship between MT levels and apoptosis sensitivity.
Main Results:
- A strong negative linear correlation (r = -0.991) was observed between basal MT levels and etoposide-induced apoptosis.
- Cadmium and zinc pretreatment increased MT levels and significantly decreased etoposide-induced apoptosis in HepG2 cells.
- Induced MT levels showed a strong negative correlation (r = -0.965) with sensitivity to etoposide-induced apoptosis.
Conclusions:
- Metallothionein (MT) plays a significant role in regulating cellular apoptosis.
- Increased MT expression is associated with decreased sensitivity to etoposide-induced apoptosis.
- Modulating MT expression may represent a novel strategy to enhance chemotherapy efficacy by altering cellular resistance.