Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells.
ABSTRACT 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.
- Nutrition 02/2004; 20(1):89-94. · 2.86 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Unfolded or misfolded proteins in the endoplasmic reticulum (ER) must be refolded or degraded to maintain homeostasis of the ER. The ATF6 and IRE1-XBP1 pathways are important for the refolding process in mammalian cells; activation of these transcriptional programs culminates in induction of ER-localized molecular chaperones and folding enzymes. We show here that degradation of misfolded glycoprotein substrates requires transcriptional induction of EDEM (ER degradation-enhancing alpha-mannosidase-like protein), and that this is mediated specifically by IRE1-XBP1 and not by ATF6. As XBP1 is produced after ATF6 activation, our results reveal a time-dependent transition in the mammalian unfolded protein response: an ATF6-mediated unidirectional phase (refolding only) is followed by an XBP1-mediated bidirectional phase (refolding plus degradation) as the response progresses.Developmental Cell 03/2003; 4(2):265-71. · 12.86 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: 3,4-dihydroxyphenylethanol (hydroxytyrosol; DPE) is the major phenolic antioxidant present in extra virgin olive oil, either in a free or esterified form. Despite its relevant biological effects, no data are available on its bioavailability and metabolism. The aim of the present study is to examine the molecular mechanism of DPE intestinal transport, using differentiated Caco-2 cell monolayers as the model system. The kinetic data demonstrate that [(14)C]DPE transport occurs via a passive diffusion mechanism and is bidirectional; the calculated apparent permeability coefficient indicates that the molecule is quantitatively absorbed at the intestinal level. The only labelled DPE metabolite detectable in the culture medium by HPLC (10% conversion) is 3-hydroxy-4-methoxyphenylethanol, the product of catechol-O-methyltransferase; when DPE is assayed in vitro with the purified enzyme a K(m) value of 40 microM has been calculated.FEBS Letters 04/2000; 470(3):341-4. · 3.58 Impact Factor