Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells
Advance Access publication May
Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells
Eunmyong Lee 1 2 3
Moon-Kyung Choi 1 2
Young-Ju Lee 1 2
Ja-Lok Ku 0 2
Kyung-Hee Kim 0 2
Jin-Sung Choi 0 2
Soo-Jeong Lim 1 2 3
0 Laboratory of Cell Biology, Cancer Research Center and Cancer Research Institute, Seoul National University College of Medicine , Seoul , Korea
1 Research Institute, National Cancer Center , Goyang, Gyeonggi , Korea
2 and Biotechnology, Sejong University , 98 Kunja-dong, Kwangjin-gu, Seoul 143-747 , Korea. Tel:
3 Department of Bioscience and Biotechnology, Sejong University , Seoul , Korea
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The production of prostaglandin E2 (PGE2), a key
proinflammatory mediator, is regulated by the availability
of its substrate, arachidonic acid (AA), and the activity
of the enzyme cyclooxygenase (COX). Increased PGE2
production and COX-2 expression have been observed
frequently in specimens from lung cancer patients. Agents
that decrease PGE2 production may prevent the initiation
and progression of lung cancer. We, therefore, tested
the effects of alpha-tocopherol (aTOL) analogs on PGE2
production in human lung epithelial cells.
Alphatocopheryl succinate (aTOS), but not aTOL or
alphatocopheryl acetate (aTOA), inhibited the phorbol
12-myristate 13-acetate (PMA)-stimulated PGE2
production in three human lung epithelial cell lines (BEAS-2B,
H460 and A549 cells). The effect of these compounds on
PGE2 production was not correlated with their
antioxidant activities, since aTOS alone did not inhibit
PMAinduced generation of reactive oxygen species. aTOS had
no effect on PMA-induced AA release or COX-2
expression, although post-incubation with aTOS inhibited
COX activity and prostaglandin (PGE2 and PGF2a)
production in PMA-stimulated cells. aTOS also blocked
the COX activity in A549 cells with endogenous high levels
of COX enzymes in the absence of PMA stimulation. In
addition, the ability of aTOS to inhibit COX was affected
by AA concentration, suggesting that aTOS may compete
with AA for interaction with COX proteins. These results
suggest that aTOS inhibits COX activity, thereby
inhibiting PGE2 production in human lung epithelial cells,
despite the lack of antioxidant activity. Administration of
aTOS may block inflammatory responses mediated by
PGE2, thereby inhibiting the initiation and progression of
lung cancer.
Introduction
Chronic inflammation is a major contributor to the
development of degenerative diseases, including cancer,
cardiovascular diseases and neurodegenerative disorders (1).
Inflammatory mediators such as cytokines and eicosanoids
are critical for the initiation and maintenance of cancer cell
survival and growth. For example, the concentration of
prostaglandin E2 (PGE2) is higher in tumor tissues than in
normal tissues (2). In tumor cells, PGE2 has been found to
inhibit apoptosis and induce proliferation (3). PGE2 also
increases tumor progression by altering cell morphology and
by increasing cell motility and migration. Therefore, specific
inhibition of PGE2 production may suppress tumor initiation
and progression.
The production of PGE2 begins with the liberation of
arachidonic acid (AA) from membrane phospholipids by
phospholipase A2 (PLA2). Subsequently, cyclooxygenase
(COX) enzymes convert AA to PGH2 (prostagladin H2),
which is converted to various prostaglandins (PGs), including
PGE2. Therefore, PGE2 production can be regulated by both
substrate availability and COX enzyme activity (4). Of the
two isoforms of COX, COX-1 is expressed constitutively in
most tissues of the body and acts as a housekeeper enzyme,
whereas COX-2 is induced by cytokines, growth factors,
carcinogens and tumor promoters (5).
Antioxidant vitamins, which protect against oxidants such
as those produced during inflammation, are believed to be
important in cancer prevention, primarily by inhibiting
inflammatory responses (1). Alpha-tocopherol (aTOL), one
of vitamin E family members, has a potent antioxidant
activity and it is the predominant form of vitamin E in
vitamin supplements (6). aTOL also has antithrombotic,
anticoagulant, neuroprotective, antiproliferative,
immunomodulatory, cell membrane-stabilizing and antiviral actions,
which may or may not be associated with its antioxidant
activity (7,8). aTOL has been found to suppress PGE2
production. For example, aTOL was shown to suppress the
oxidized low-density lipoprotein (LDL)-induced PLA2
activity in rat mesangial cells (9) and to attenuate
lipopolysaccharide (LPS)-induced COX-2 transcription and synthesis in
microglial cells (10). In macrophage cells and aged mice,
aTOL and its analog alpha-tocopheryl acetate (aTOA) have
been found to decrease COX activity but to have no effect on
the level of expression of COX mRNA and protein (11,12).
Taken together, these findings suggest that supplementation
with aTOL may be beneficial in preventing diseases related
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