Carcinogenesis Advance Access published online on March 7, 2006
Carcinogenesis, doi:10.1093/carcin/bgl009
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1 INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, BP 416, F-75018, Paris, France; Université Paris 7 Denis Diderot, site Bichat, BP 416, F-75018, Paris, France
* To whom correspondence should be addressed. 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
Received December 6, 2005
Revised February 11, 2006
Accepted March 3, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells
Cécile Guichard 1 
,
Eric Pedruzzi 1 ,
Michèle Fay 1,
Jean-Claude Marie 1,
Françoise Braut-Boucher 1,
Fanny Daniel 1,
Alain Grodet 1,
Marie-Anne Gougerot-Pocidalo 1,
Eric Chastre 1,
Larissa Kotelevets 1,
Gérard Lizard 2,
Alain Vandewalle 1,
Fathi Driss 3,
and
Eric Ogier-Denis 1 *
2 INSERM U498 CHU du Bocage, Laboratoire de Biochimie Médicale, BP77908, 21019 Dijon Cedex, France
3 Hôpital X. Bichat, Service de Biochimie Hormonale et Génétique, 46 rue Henri Huchard, 75018 Paris, France
Eric Ogier-Denis, E-mail: ogier{at}bichat.inserm.fr
Abstract 
arms. DPE treatment led to overexpression of the pro-apoptotic factor CHOP/GADD153, and persistent activation of the Jun-NH2-terminal kinase (JNK)/AP-1 signaling pathway. DPE concomitantly modulated the Erk1/2 and Akt/PKB pro-survival factors by altering their phosphorylation status as well as inhibiting TNF--induced NF-
B activation by inactivating the phosphorylation of I-B kinase (IKK
). 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 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.These authors contributed equally to this work.
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