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Isolation of a chemical inhibitor against K-Ras-induced p53 suppression through natural compound screening
Su-Jin Lee1, Youn-Sang Jung, Sun-Hye Lee
1Department of Molecular Biology, College of Natural Science, Pusan National University, Jangjeon-dong, Geumjoung-gu, Busan, Korea.
Abstract:
The strong tumor suppressor p53 shows loss of function in large portion of human cancer. In addition to genetic mutation, biological function of p53 is suppressed by signaling distortion or elevated expression of p53 inhibitors (such as overexpression of MDM2 or deletion of p14/ARF). In this study, we demonstrate that K-Ras, a frequently altered oncogene in human cancers including pancreatic cancer (about 80%), colon cancer (45%) and lung cancer (45%), suppresses p53. Based on this fact, we perform Western blot analysis-based chemical screening to isolate a K-Ras-specific activator of p53. From 117 kinds of chemicals (34 kinds of natural compounds that are obtained from herbal plants, 53 kinds of flavonoid, and 31 kinds of phenolic compounds), we find that quercetin works as an activator of p53 in K-Ras mutated cells but not in wild-type cells. Treatment with quercetin can induce p53 target genes such as PUMA and p21. These results suggest that although quercetin has limitations for use as a therapeutic drug due to its broad effects, specific function of it on K-Ras-p53 may be useful for K-Ras-induced cancer prevention and therapy through further development.
Insights
Quercetin activates the tumor suppressor p53 in cancer cells with K-Ras mutations, a common oncogene. This suggests potential for developing K-Ras-driven cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The tumor suppressor p53 is frequently inactivated in human cancers through genetic mutations or altered signaling pathways.
- K-Ras, a common oncogene in pancreatic, colon, and lung cancers, suppresses p53 function.
- Inhibitors like MDM2 overexpression or p14/ARF deletion also contribute to p53 inactivation.
Purpose of the Study:
- To identify specific activators of p53 in the context of K-Ras mutations.
- To screen chemical compounds for their ability to restore p53 activity in K-Ras-mutated cancer cells.
Main Methods:
- Western blot analysis was employed for chemical screening.
- A diverse library of 117 compounds, including natural products, flavonoids, and phenolic compounds, was tested.
- Assays focused on identifying K-Ras-specific p53 activators.
Main Results:
- Quercetin was identified as a p53 activator specifically in K-Ras-mutated cells, not in wild-type cells.
- Treatment with quercetin induced the expression of p53 target genes, including PUMA and p21.
- The study screened 34 natural compounds, 53 flavonoids, and 31 phenolic compounds.
Conclusions:
- Quercetin demonstrates specific activity as a p53 activator in K-Ras-mutated cancer cells.
- While quercetin has limitations for direct therapeutic use due to broad effects, its K-Ras-p53 interaction warrants further investigation for cancer prevention and therapy development.
