Enhanced sensitivity of human oral tumours to the flavonol, morin, during cancer progression: involvement of the Akt and stress kinase pathways.
Various naturally occurring flavonoids have been found to be cancer-protective in chemically induced animal cancer models and synthetic flavonoid derivatives are being tested for potential chemotherapeutic usefulness in clinical trials. This report demonstrates that human oral squamous carcinoma cells (SCC) are significantly more sensitive to growth inhibition by the naturally occurring flavonoid, morin (3,5,7,2',4'-pentahydroxyflavone) than normal oral mucosa (NOMC) (SCC IC(50) = 115 microM; NOMC IC(50) = 173 micro M; P for difference = 0.009). Structure/function comparisons indicate that both the 2' and 4' hydroxyl groups in morin are required for its tumour selectivity. Morin causes growth arrest in G(2)/M, without inducing apoptosis, and this is associated with induction of GADD45 and phosphorylation and inactivation of the cell cycle kinase, cdc2. Morin also has pleiotropic effects on kinase signalling pathways, including inhibition of activation of protein kinase B by mitogens (but not extracellular-regulated kinases 1/2) and activation of the stress pathway kinases, Jun N-terminal kinase and p38 kinase. p38 kinase activation is functionally important since inhibition of its activation by the specific inhibitor SB202190 partially prevented cell cycle arrest by morin. However, analysis of dose-response relationships reveals that the enhanced tumour sensitivity to morin may be explained by the fact that activation of AKT is inhibited at lower concentrations of morin in carcinomas than normal oral mucosa, whereas Jun N-terminal kinase, p38 kinase and GADD45 are all induced in parallel with the same dose-response curves in carcinomas and normal oral mucosa.
Brown
Judith
J
The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
O'Prey
Jim
J
Harrison
P R
PR
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects*; D006224:Cricetinae; D004789:Enzyme Activation; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D047309:Flavones
D005419:Flavonoids; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C008548:morin; D047309:Flavones; C494918:AKT1 protein, human