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What is PPAR-?
Peroxisome proliferator-activated receptor-gamma: member of the steroid nuclear hormone receptor superfamily
Three types of PPAR, encoded by separate genes: , each with own set of prefered ligands
PPAR- ligands: Thiazolidone class of drugs (ciglitazone, triglitazone,
rosiglitazone (Avandia- GSK, oral hypoglycemic drug)15-dPGJ2
Fatty acids
PPAR- has a role in adipocyte differentiation and fat metabolism.
Does PPAR- have a role in carcinogenesis?
Inhibit cancer: PPAR- activators can inhibit growth of breast cancer cell lines in vitro by increasing sensitization to apoptosis. Reported to Inhibit in vivo growth in xenogeneic system (nude mice) and various in vivo cancer models.
Promote cancer: Two reports that thiazolidone drugs promote colon cancer in animal models.
Lisa’s data (J. Nutrition, 2005) is inconclusive: in vitro data indicates that PPAR- inhibits tumor growth. In vivo data is another story- leans towards being pro-tumor (still a lot of questions).
What about skin cancer?
PPAR- in skin cancer
PPAR- +/- mice are more susceptible to DMBA-induced skin papilloma development compared to PPAR-g +/+ (wt) mice (Nicol et al, Carcinogenesis, 2004).
In human skin, PPAR- associated with keratinocyte differentiation: supra-basal cells only (Westergaard et al, JID, 2001).
In vitro, PPAR-g ligands inhibit growth of cultured mouse keratinocytes. However, PPAR- protein was not detected in the keratinocytes (He et al, JID,2004).
UV 3x/week for 15 weeks(90mJ/cm2 start, increase 10% weekly to 175mJ/cm2)
Mice randomized to rosi+ or rosi- diet weeks 15-29(rosi 200ppm- very high compared to what Lisa uses- 12mg/kg)
Tu
mo
rs/m
ou
se%
mic
e w
ith
tu
mo
rs
No difference
Effect of Dietary Rosiglitazone on UV Skin Carcinogenesis
Effect of Topical Troglitazone on UV carcinogenesis
Tu
mo
rs/m
ou
se%
mic
e w
ith
tu
mo
rs
UV 3x/week then topical treatment with 100g troglitazone or acetone
No significant effect
Effect of Dietary Rosi on DMBA/TPA skin carcinogenesis
Tu
mo
rs/m
ou
se%
mic
e w
ith
tu
mo
rs
FVB/n mice, shaved, 100g DMBA, at 2 weeks, 3x/week treatment with 2.5g TPA
Mice randomized to rosi+ or rosi- diet weeks 2-17(rosi 300ppm- very high compared to what Lisa uses- 12mg/kg)
No significant effect
2000ppm troglitazone for 1 week
TPA or vehicle, then inject with BrdU
Inhibits control proliferation, but not TPA-induced proliferation
Effect of dietary Troglitazone on BrdU labeling (epidermal proliferation)
PPAR-mRNA(Northern blot)
F= fatP=primary keratinocyteE= epidermisW= whole skinT= tumor
FVB/N
FVB/N
SKH
Conclusions from this paper
PPAR- ligands did not significantly alter skin tumor development when used at 200-2000ppm
Lisa uses dietary Rosiglitazone and Fish oil to activate PPAR-
In breast cancer: Fish oil protective, PPAR- does not appear to be protective (still trying to figure out what’s going on
model specific (Her-2/neu Tg mice)dose of Rosi (12mg/kg vs 200ppm)
In human studies, TGF- induces PPAP- and inhibits CTL restimulation. Further, PPAR- ligand ciglitazone induces PPAR- and alters APC function so that CTL restimulation is inhibited (Kelly’s expts)
What about fish oil and Rosi in UV inflammation and carcinogenesis?
Stimulation Index, 4 week diet
1.95
2
2.05
2.1
2.15
2.2
2.25
2.3
2.35
chow fish oil corn oil
Sti
mu
lati
on
In
dex
Avg food consumption/mouse/group
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
chow fish corn fish+rosi corn+rosi
avera
ge f
ood
(g
)
6 week diet, weights
15
17
19
21
23
25
27
29
31
33
35
6.24.05 7.1.05 7.8.05 7.15.05 7.22.05 7.29.05
dates
ave
rag
e w
eig
ht
(g)
chow fish oil corn oil fish oil+rosi corn oil + rosi
fish
Fish+ rosi
Skin Thickness 6wk-48hr
0
0.2
0.4
0.6
0.8
1
1.2
1.4
chow fish oil corn oil fish+rosi corn+rosi
Skin
th
ickn
ess (
mm
)
* **
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