Curcumin induces apoptotic cell death via Oct4 inhibition and GSK-3β activation in NCCIT cells
Ji Ho Yun1,2, Young Gyun Park1,3, Kyung-Mi Lee1
1Natural Products Research Center, KIST Gangneung Institute, Gangneung, Gangwon-do, Korea.
Scope:
Octamer-binding transcription factor 4 (Oct4) is a key regulator of pluripotent embryonic stem cell maintenance. However, increasing evidence has suggested that Oct4 is also expressed in cancer stem cells (CSCs) and is associated with tumor progression and chemoresistance. Curcumin (CUR) is a widely used cancer chemopreventive agent, and it has been used to treat several diseases including cancers. Here, we investigated whether CUR-induced apoptotic cell death by inhibiting Oct4 levels and examining molecular mechanisms in NCCIT human embryonic carcinoma cells.
Methods And Results:
CUR significantly inhibited Oct4 transcription levels in a dose-dependent manner by dual luciferase experiment, also decreased mRNA and protein levels in NCCIT human embryonic carcinoma cells, which express high levels of endogenous Oct4. Interestingly, we found that CUR treatment increased apoptotic cell death including subG0/G1 contents, cleavage caspases, and pro-apoptotic protein, as confirmed with a series of loss-of-function experiments using Oct4 siRNA. Furthermore, CUR induced marked total level of glycogen synthase kinase 3 beta (GSK-3β), resulting in an increase in apoptotic cell death, was evaluated using chemical inhibitor of GSK3-3β.
Conclusion:
These data suggest that CUR induces apoptotic cell death through Oct4 inhibition and GSK-3β activation. Thus, CUR may be a useful cancer chemopreventive agent to suppress tumor progression or to improve chemoresistance by eliminating CSCs.
Insights
Curcumin (CUR) inhibits Octamer-binding transcription factor 4 (Oct4) in cancer cells, promoting apoptosis and potentially enhancing cancer prevention and chemoresistance by targeting cancer stem cells (CSCs).
Area of Science:
- Cancer Biology
- Stem Cell Research
- Pharmacology
Background:
- Octamer-binding transcription factor 4 (Oct4) is crucial for embryonic stem cell maintenance.
- Oct4 is also found in cancer stem cells (CSCs), correlating with tumor progression and chemoresistance.
- Curcumin (CUR) is a known cancer chemopreventive agent.
Purpose of the Study:
- To investigate if CUR induces apoptotic cell death by inhibiting Oct4 levels in NCCIT human embryonic carcinoma cells.
- To elucidate the molecular mechanisms underlying CUR's effects on Oct4 and apoptosis.
- To explore the potential of CUR as a therapeutic agent against CSCs.
Main Methods:
- Dual luciferase assays to measure Oct4 transcription levels.
- Quantitative analysis of Oct4 mRNA and protein expression.
- Apoptosis assays (subG0/G1 content, caspase cleavage) and loss-of-function experiments (Oct4 siRNA).
- Western blot analysis for glycogen synthase kinase 3 beta (GSK-3β) levels and evaluation using GSK-3β inhibitors.
Main Results:
- CUR significantly inhibited Oct4 transcription, mRNA, and protein levels in a dose-dependent manner.
- CUR treatment increased apoptotic cell death, including caspase activation and pro-apoptotic protein expression.
- CUR induced GSK-3β activation, contributing to increased apoptotic cell death.
Conclusions:
- CUR induces apoptotic cell death in cancer cells by inhibiting Oct4 and activating GSK-3β.
- CUR demonstrates potential as a cancer chemopreventive agent by suppressing tumor progression and enhancing chemoresistance.
- Eliminating CSCs through CUR treatment may offer a strategy to combat cancer recurrence and improve treatment outcomes.
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