Carcinogenesis Advance Access originally published online on March 7, 2006
Carcinogenesis 2006 27(9):1812-1827; doi:10.1093/carcin/bgl009
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Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells
INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, and Université Paris 7 Denis Diderot site Bichat, BP 416, F-75018, Paris, France
1 INSERM U498 CHU du Bocage, Laboratoire de Biochimie Médicale BP77908, 21019 Dijon Cedex, France
2 Hôpital X. Bichat, Service de Biochimie Hormonale et Génétique 46 rue Henri Huchard, 75018 Paris, France
*To whom correspondence should be addressed. Tel. +33 1 4485 6211; Fax: +33 1 4485 6207; Email: ogier{at}bichat.inserm.fr
The search for effective chemopreventive compounds is a major challenge facing research into preventing the progression of cancer cells. The naturally occurring polyphenol antioxidants look very promising, but their mechanism of action still remains poorly understood. Here, we show that 2-(3,4-dihydroxyphenyl)ethanol (DPE), a phenol antioxidant derived from olive oil, induces growth arrest and apoptosis in human colon carcinoma HT-29 cells. The mechanisms involve prolonged stress of the endoplasmic reticulum (ER) leading to the activation of the two main branches of the unfolded protein response (UPR), including the Ire1/XBP-1/GRP78/Bip and PERK/eIF2
arms. DPE treatment led to overexpression of the pro-apoptotic factor CHOP/GADD153 and persistent activation of the Jun-NH2-terminal kinase/activator protein-1 signaling pathway. DPE concomitantly modulated the extracellular signal-regulated kinase 1/2 and Akt/PKB pro-survival factors by altering their phosphorylation status as well as inhibiting tumor necrosis factor--induced nuclear factor-
B activation by inactivating the phosphorylation of nuclear factor inhibitor-B kinase. These findings prompted us to investigate the possible involvement of phosphatases in DPE-mediated action. Using phosphatase inhibitors and RNA interference to silence the Ser/Thr phosphatase 2A (PP2A) prevented DPE-induced cell death. These findings demonstrate that DPE specifically activates PP2A, which plays a key initiating role in various pathways that lead to apoptosis in colon cancer cells.
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