***** seminarMLから情報転載 *****


日時:平成20年6月19日(木) 午後4:00~5:00

会場:(財)東京都医学研究機構 東京都臨床医学総合研究所 2階会議室

演題:Altered Arachidonic Acid Balance and Colon Cancer

演者:Daniel W. Rosenberg&s_comma; Ph.D.
Professor of Medicine&s_comma; Genetics and Developmental Biology; Co-Director&s_comma;
Colon Cancer Prevention Program; University of Connecticut Health Center&s_comma;
Farmington&s_comma; CT

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths
in the U.S.&s_comma; and 1 in 18 persons are diagnosed with CRC over the course of a
lifetime. Risk factors are often associated with environmental and dietary
exposures&s_comma; including consumption of red meat and high fat intake. As
prostaglandin (PG) metabolites have been shown to contribute to colorectal
cancer growth&s_comma; non-steroidal anti-inflammatory drugs&s_comma; including
cyclooxygenase-2 (COX-2) inhibitors&s_comma; are among the most promising
chemopreventive agents for CRC. However&s_comma; their long-term use is restricted
by the occurrence of adverse events believed to be associated with among
other things&s_comma; enhanced intestinal permeability. Using knockout mice for
enzymes responsible for PG biosynthesis&s_comma; Dr. Rosenberg provides new lines of
information regarding the mechanisms of toxicity associated with COX-2
inhibition. Arachidonic acid (AA) is generated in tumor cells by the
actions of both secretory and intracellular phospholipase A2 (PLA2) enzymes.
Cytosolic phospholipase A2 (cPLA2a) contributes to the production of
cancer-promoting prostaglandins via the COX-2-catalyzed conversion of AA.
Additionally&s_comma; cPLA2a regulation of intracellular AA levels affects apoptotic
signaling&s_comma; as AA not consumed by COX-2 may control the conversion of
sphingomyelin to ceramide&s_comma; a key death effector. Studies using mice that
are deficient in cPLA2a provide evidence that the growth inhibitory role of
cPLA2a through regulating apoptosis may play an important role in intestinal
tumorigenesis. A long-standing interest in the role of sPLA2 in intestinal
tumorigenesis will also be discussed. Metabolism of AA by COX-2 generates
PGE2&s_comma; a bioactive lipid that mediates a wide range of physiological effects
implicated in inflammation and cancer. Evidence for the chemopreventive
efficacy of targeting the terminal microsomal PGE2 synthase 1 (mPGES-1)&s_comma;
which is responsible for generating PGE2&s_comma; in two murine models of intestinal
cancer&s_comma; including mechanisms that may account for this observed suppression
in intestinal tumor promotion&s_comma; will be presented. Taken together&s_comma; these
works clearly demonstrate that modulation of AA metabolism plays a critical
role in intestinal disease pathogenesis.

世話人:東京都臨床医学総合研究所 細胞膜情報伝達プロジェクト1 村上 誠
電話:03-3823-2105 (代) 内線5200
E-mail: mako@rinshoken.or.jp