Peroxisome proliferator-activated receptor gamma and spermidine/spermine N1-acetyltransferase gene expressions are significantly correlated in human colorectal cancer.
BACKGROUND
The peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor that regulates adipogenic differentiation and glucose homeostasis. Spermidine/spermine N1-acetyltransferase (SSAT) and ornithine decarboxylase (ODC) are key enzymes involved in the metabolism of polyamines, compounds that play an important role in cell proliferation. While the PPARgamma role in tumour growth has not been clearly defined, the involvement of the altered polyamine metabolism in colorectal carcinogenesis has been established. In this direction, we have evaluated the PPARgamma expression and its relationship with polyamine metabolism in tissue samples from 40 patients operated because of colorectal carcinoma. Since it is known that the functional role of K-ras mutation in colorectal tumorigenesis is associated with cell growth and differentiation, polyamine metabolism and the PPARgamma expression were also investigated in terms of K-ras mutation.


METHODS
PPARgamma, ODC and SSAT mRNA levels were evaluated by reverse transcriptase and real-time PCR. Polyamines were quantified by high performance liquid chromatography (HPLC). ODC and SSAT activity were measured by a radiometric technique.


RESULTS
PPARgamma expression, as well as SSAT and ODC mRNA levels were significantly higher in cancer as compared to normal mucosa. Tumour samples also showed significantly higher polyamine levels and ODC and SSAT activities in comparison to normal samples. A significant and positive correlation between PPARgamma and the SSAT gene expression was observed in both normal and neoplastic tissue (r = 0.73, p < 0.0001; r = 0.65, p < 0.0001, respectively). Moreover, gene expression, polyamine levels and enzymatic activities were increased in colorectal carcinoma samples expressing K-ras mutation as compared to non mutated K-ras samples.


CONCLUSIONS
In conclusion, our data demonstrated a close relationship between PPARgamma and SSAT in human colorectal cancer and this could represent an attempt to decrease polyamine levels and to reduce cell growth and tumour development. Therefore, pharmacological activation of PPARgamma and/or induction of SSAT may represent a therapeutic or preventive strategy for treating colorectal cancer.
Linsalata
Michele
M
Laboratory of Biochemistry, National Institute for Digestive Diseases, I.R.C.C.S. Saverio de Bellis via Della Resistenza, 70013-Castellana Grotte (BA), Italy. m.linsalata@libero.it
Giannini
Romina
R
Notarnicola
Maria
M
Cavallini
Aldo
A
D000123:Acetyltransferases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009955:Ornithine Decarboxylase / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011073:Polyamines / Q000032:analysis; D013223:Statistics as Topic; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D009955:Ornithine Decarboxylase; D047495:PPAR gamma; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase