Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells.
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/eIF2alpha 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-alpha-induced nuclear factor-kappaB activation by inactivating the phosphorylation of nuclear factor inhibitor-kappaB 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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INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, and Université Paris 7 Denis Diderot, site Bichat, and Hôpital X. Bichat, Service de Biochimie Hormonale et Génetique, Paris, France.
Pedruzzi
Eric
E
Fay
Michèle
M
Marie
Jean-Claude
JC
Braut-Boucher
Françoise
F
Daniel
Fanny
F
Grodet
Alain
A
Gougerot-Pocidalo
Marie-Anne
MA
Chastre
Eric
E
Kotelevets
Larissa
L
Lizard
Gérard
G
Vandewalle
Alain
A
Driss
Fathi
F
Ogier-Denis
Eric
E
D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C005975:3,4-dihydroxyphenylethanol; C503981:PPP2R5C protein, human; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D010626:Phenylethyl Alcohol