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Protein synthesis inhibition by flavonoids: roles of eukaryotic initiation factor 2alpha kinases
1Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, 77555-1048, USA.
Abstract:
Flavonoids such as genistein and quercetin suppress tumor cell growth in vitro and in vivo. Many metabolic enzymes, including protein kinases, are known to be inhibited by flavonoids, yet the molecular targets and biochemical mechanisms of the tumor growth suppression remain unclear. Here, we find that flavonoids inhibit protein synthesis in both mouse and human leukemia cells. This inhibition is associated with phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha), a key regulatory mechanism of protein translation. Three mammalian eIF2alpha kinases have been identified: the interferon-inducible double-stranded RNA-dependent kinase (PKR), the heme-regulated inhibitor (HRI), and the very recently discovered PERK/PEK. We find that all of these eIF2alpha kinases can be activated by quercetin and genistein, indicating redundant roles of the eIF2alpha kinases. Thus, activation of eIF2alpha kinases appears to be a mechanism by which flavonoids can inhibit the growth of tumor and leukemia cells.
Insights
Flavonoids like genistein and quercetin inhibit tumor cell growth by blocking protein synthesis. This occurs through the activation of eukaryotic initiation factor 2 alpha (eIF2alpha) kinases, offering a new therapeutic target for leukemia.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Flavonoids, including genistein and quercetin, show anti-tumor effects in vitro and in vivo.
- The precise molecular targets and mechanisms underlying flavonoid-induced tumor suppression are not fully understood.
- Protein kinases are known targets of flavonoids, but their role in tumor growth inhibition requires further elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms by which flavonoids inhibit tumor cell growth.
- To identify the specific targets of flavonoids involved in protein synthesis regulation.
- To explore the role of eukaryotic initiation factor 2 alpha (eIF2alpha) kinases in flavonoid-mediated anti-cancer effects.
Main Methods:
- Assessing the impact of flavonoids on protein synthesis in mouse and human leukemia cells.
- Analyzing the phosphorylation status of eukaryotic initiation factor 2 alpha (eIF2alpha).
- Investigating the activation of mammalian eIF2alpha kinases: PKR, HRI, and PERK/PEK by quercetin and genistein.
Main Results:
- Flavonoids were found to inhibit protein synthesis in leukemia cells.
- Flavonoid treatment led to the phosphorylation of eIF2alpha, a key regulator of protein translation.
- Quercetin and genistein were shown to activate all three identified mammalian eIF2alpha kinases (PKR, HRI, PERK/PEK).
Conclusions:
- Flavonoid-induced inhibition of protein synthesis is mediated by the activation of eIF2alpha kinases.
- The activation of eIF2alpha kinases by flavonoids represents a significant mechanism for suppressing tumor and leukemia cell growth.
- These findings suggest that targeting eIF2alpha kinases could be a therapeutic strategy for cancer treatment.