Isolation of a chemical inhibitor against K-Ras-induced p53 suppression through natural compound screening.
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.
Department of Molecular Biology, College of Natural Science, Pusan National University, Jangjeon-dong, Geumjoung-gu, Busan, Korea.
Su-Jin
SJ
Lee
Youn-Sang
YS
Jung
Sun-Hye
SH
Lee
Hye-Young
HY
Chung
Bum-Joon
BJ
Park
D000975:Antioxidants / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011794:Quercetin / Q000494:pharmacology*; D013678:Technology, Pharmaceutical; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011794:Quercetin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins