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Se-methylselenocysteine sensitized TRAIL-mediated apoptosis via down-regulation of Bcl-2 expression
Jung Tae Lee1, Tae-Jin Lee, Jong-Wook Park
1Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Jung-Gu, Taegu 700-712, Korea.
Abstract:
Recent studies establish a critical role of selenium in cancer prevention in vitro and in vivo. Selenium may sensitize TRAIL-mediated apoptosis in human renal cancer cells and increase therapeutic efficacy. In this study, we demonstrate that concomitant administration of TRAIL and Se-methylselenocysteine (Se-MSC) produces synergistic effects on the induction of apoptosis in Caki cells. Se-MSC rapidly and specifically down-regulates expression of the Bcl-2 at transcriptional level. The forced expression of Bcl-2 attenuated Se-MSC plus TRAIL-mediated apoptosis, suggesting that the lessened Bcl-2 expression caused by Se-MSC treatment is critical to the increased sensitivity to TRAIL in renal cancer cells. In addition, we demonstrate that the synergistic effects of Se-MSC and TRAIL result from the activation of the caspase-dependent pathways. Co-administration of HA14-1, a small molecule Bcl-2 inhibitor and TRAIL increased apoptosis in Caki cells. Taken together, Se-MSC-mediated down-regulation of Bcl-2 is able to sensitize Caki cells for TRAIL-induced apoptosis. Thus, selenium-based dietary compounds may help to overcome resistance to TRAIL-mediated apoptosis in renal cancer cells.
Insights
Selenium, specifically Se-methylselenocysteine (Se-MSC), enhances TRAIL-induced apoptosis in renal cancer cells. This occurs by down-regulating Bcl-2 expression, making cancer cells more sensitive to TRAIL therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Selenium plays a role in cancer prevention.
- Selenium compounds may enhance TRAIL-mediated apoptosis in renal cancer.
- Understanding mechanisms of TRAIL resistance is crucial for cancer therapy.
Purpose of the Study:
- To investigate the synergistic effects of TRAIL and Se-methylselenocysteine (Se-MSC) on renal cancer cells.
- To elucidate the role of Bcl-2 in Se-MSC and TRAIL-induced apoptosis.
- To explore the signaling pathways involved in the combined treatment.
Main Methods:
- Treatment of Caki cells with TRAIL and Se-MSC.
- Analysis of Bcl-2 expression at the transcriptional level.
- Forced expression of Bcl-2 to assess its role in apoptosis.
- Investigation of caspase-dependent pathways.
- Co-administration of TRAIL with a Bcl-2 inhibitor (HA14-1).
Main Results:
- Concomitant administration of TRAIL and Se-MSC induced synergistic apoptosis in Caki cells.
- Se-MSC significantly down-regulated Bcl-2 expression transcriptionally.
- Forced Bcl-2 expression attenuated the apoptotic effects of Se-MSC plus TRAIL.
- The synergistic effects involved activation of caspase-dependent pathways.
- Combined treatment with HA14-1 and TRAIL also increased apoptosis.
Conclusions:
- Se-MSC down-regulates Bcl-2, sensitizing renal cancer cells to TRAIL-induced apoptosis.
- Selenium-based compounds may offer a strategy to overcome TRAIL resistance in renal cancer.
- The findings highlight the potential of combining selenium with TRAIL therapy for improved cancer treatment.
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