Epidermal growth factor-responsive laryngeal squamous cancer cell line Hep2 is more sensitive than unresponsive CO-K3 one to quercetin and tamoxifen apoptotic effects.
Epidermal growth factor receptor (EGFR) plays a role in laryngeal squamous cell carcinoma (SCC) development and progression. The flavonoid quercetin (Q) and the antiestrogen tamoxifen (TAM) inhibit proliferation of both primary laryngeal SCC and laryngeal carcinoma cell lines, through still uncharacterized mechanisms. We studied Q and TAM inhibitory effect on epidermal growth factor (EGF)-stimulated Hep2 and CO-K3 laryngeal squamous cell lines. Q and TAM (0.1-1.0 microM) induced more apoptosis in EGF growth-stimulated than in unstimulated Hep2 cells. EGF neither stimulated CO-K3 cell growth nor enhanced Q and TAM-induced apoptosis. Mitogen-activated protein kinase (MAPK) analysis revealed that in Hep2 cells, but not in CO-K3 cells, EGF induced a time-dependent phosphorylation of p42, p44, p38, and p46. In Hep2 cells, but not in CO-K3 cells, Q and TAM produced, upon EGF treatment, a twofold increase of p38 and p46 and an enhancement of p42 and p44 dephosphorylation, suggesting a requirement of EGFR. The enhancing effect was due to a p38 and p46 dephosphorylation delayed kinetics. An antiphosphorylated p38 antibody prevented Q and TAM inhibitory effect on p42 and p44 phosphorylations, suggesting that the EGF-dependent increase in Q and TAM apoptotic effect on Hep2 cells could depend on the p38 inhibition of the survival kinases p42 and p44. In SCC, EGFR overexpression is an early event from dysplasia to neoplasia. We conclude that the capacity of Q and TAM to increase apoptosis in EGFR-activated cells makes these compounds possible chemopreventive drugs in subjects at risk of developing laryngeal cancer.
Raspaglio
G
G
Department of Gynecology/Obstetrics, Catholic University, L.go A. Gemelli, 8, 00168, Rome, Italy.
Ferrandina
G
G
Ferlini
C
C
Scambia
G
G
Ranelletti
F O
FO
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000096:biosynthesis; D006801:Humans; D007822:Laryngeal Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011794:Quercetin / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors
D016588:Anticarcinogenic Agents; D013629:Tamoxifen; D004815:Epidermal Growth Factor; D011794:Quercetin; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases