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APC gene [154]. The APC protein takes place
in the Wnt/ f3-catenin signalling pathway
[157]. APC and f3-catenin are phosphorylated
by glycogen synthase kinase 313 ; this process
leads to degradation of f3-catenin in a
proteasome-dependent manner. In colorectal
cancers, mutations affect the APC gene
resulting in f3-catenin stabilisation and 13­
catenin translocation into nuCleus [158].
Subsequently, f3-catenin interacts with
members of the T-Cell tians~ription factors
family (TCF, [159]) and alters transcription of
TCF-dependent target genes like c-myc [160],
cyclin Dl [161], cyclooxygenase-2 [162], c­
jun, fra-l and urokinase-type plasminogen
activator receptor [163] which are implicated
in céIl cycle progression, cell proliferation
and apoptosis and in cell to cell interactions.
In colon cancers, ppARù transcription 1evel is
up-regulated and seems to co-localise with
cyclooxygenase-2 rnRNA in the same regions
within the turnors [164]. ppARù has been
identified ,as a target gene of Tcf4, a member
of the TCF family [165]. Transfection of the
complete APC gene in a APC-mutated colon
cell line, the HT29 cell line, restores
cytoplasmic f3-catenin degradation mediated
by APC and subsequently lowers ppARf3
transcriptional level. In addition, NSAIDs
treatment decreases ppARù transcriptional
activity leading to the hypothesis that NSAIDs
protection is mediated by disruption in
ppARù-dependent target gene expression
[165]. ,
PPARyhas also been associated to colon
cancers. The two isoforms exist even though
PPARy1 is predominant [166]. However,
different studies provide opposite results :
Activation of PPARy by specific ligands is
responsible for tumor progression in APC/Min
mice or heterozygote males C57Bl/6J­
APCMin/+ [167, 168]. In contrast, in human
colon cancer cell lines, activation of PPARy
slows down their growth and consequently
inhibits expression of tumor markers and
increases transcription of proteins associated
with colon cell differentiation [169]. In
addition, development of transplantable
Hervé Schohn et al.
turnors in nude mice is lowered by treatment
with troglitazone, a PPARy ligand [168].
Thus, the role ofppARy in colorectal cancers
is speculative despite its high transcriptional
level. Furthennore, loss-of-function mutations
also affect PPARy gene in human sporadic
carcinomas altering protein function as
demonstrated by transfection studies [170].
In contrast to PPARf3/Ù and y, PPARa is not
up-regulated [171]. !ts expression in tumoral
cells is often lower than in normal tissue.
PPARyin others neoplasic processes
As stated before, thiazolidinediones are
agonists of PPARy. These drugs and 15­
deoxy-ô-12, 14 prostaglandin 12, a natural
ppARy ligand, have been used to study the
role of ppARy activation in diverse cancerderived
cell lines in vitro. Taken together,
results show that ppARy activation induces
cell cycle arrest and terminal differentiation
and/or apoptosis in malignant astrocytoma cell
line [172], in choriocarcinoma cells [173], in
human breast cancer cells [174-177], in
human gastric cancer [178-180], in pancreatic
carcinoma cells [181], in colon
adenocarcinoma ceIls [166, 169, 182, 183], in
lung cancer cells [184, 185], in myeloid
leukemia ceIl lines [186, 187], in human
prostate cancer ceIls [188] and in liposarcoma
ceIls [189]. Thus, it appears clearly from these
data that activation of ppARy has a benejic
effect by limiting cancer cell growth.
Moreover, terminal differentiation mediated
by PPARy agémists was confmned in vivo in
patients with liposarcoma [190] or prostate
cancer [191] and in mice with prostate cancer
[188] or mammary cancer [174, 192]. On the
other hand, PPARy is upregulated in human
uterine leiomyomata, benign tumors of
smooth muscle ceIls, compared with nonnal
myometrium [193].Further more, in guinea
pig, troglitazone treatment combined with
estradiol and aH trans retinoic acid produced
uterine leiomyomata whereas this ppARy
effect is not observed when troglitazone is
used alone [193].Taken together, data suggest