Resveratrol targets transforming growth factor-β2 signaling to block UV-induced tumor progression.
Resveratrol (RES) is a potent anti-cancer agent. We have previously reported that RES arrests the growth of invasive human A431 squamous cell carcinoma (SCC) cells. In this study, we show that oral administration of RES to highly tumor-susceptible p53(+/-)/SKH-1 mice markedly delayed UV-induced skin tumorigenesis and reduced the malignant conversion of benign papillomas to SCCs. Transforming growth factor-β2 (TGF-β2) was predominantly overexpressed in UV-induced SCCs and its expression was diminished in RES-treated SCCs/skin. In addition to the inhibition of TGF-β2 expression, RES increased the level of epithelial cadherin. This RES-mediated TGF-β2 downregulation led to the inhibition of both TGF-β2/Smad-dependent and -independent pathways, and suppressed the invasiveness of A431 cells. Addition of TGF-β2, but not TGF-β1, rescued the RES-mediated downregulation of p-extracellular signal-regulated kinases 1/2, p-Smad3, and α-smooth muscle actin. The protein kinase B (Akt) substrate cAMP response-binding protein (pCREB) transcription factor is known to regulate TGF-β2 expression, and RES treatment decreased phosphorylation of Akt and pCREB. Expression of constitutively active Akt blocked RES inhibition of CREB and TGF-β2, and rescued RES inhibition of cellular invasiveness. Our data indicate that RES suppresses UV-induced malignant tumor progression in p53(+/-)/SKH-1 mice and that RES-inhibited invasiveness of human A431 SCC cells appears to occur, in part, through the Akt-mediated downregulation of TGF-β2.
Kim
Kwang Ho
KH
Department of Dermatology, Columbia University Medical Center, Irving Cancer Research Center, New York, New York, USA.
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Jung Ho
JH
Zhu
Yucui
Y
Arbesman
Josh
J
Athar
Mohammad
M
Kopelovich
Levy
L
Kim
Arianna L
AL
Bickers
David R
DR
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
D016588:Anticarcinogenic Agents; D013267:Stilbenes; C509042:Tgfb2 protein, mouse; D053781:Transforming Growth Factor beta2; D016159:Tumor Suppressor Protein p53; D000077185:Resveratrol