Increased Farnesyltranferase Activity in Human Colorectal Cancer: Relationship with Clinicopathological Features and K-ras Mutation

Abstract

Background: The enzyme farnesyltransferase has emerged as an important target for anti-cancer therapies. Farnesyltranferase inhibitors have been introduced in clinical trials of subjects with colorectal cancer. We investigated Farnesyltranferase activity, 𝛃-subunit Farnesyltranferase protein expression and its mRNA in patients with colorectal cancer and its relationship with clinicopathological features and K-ras mutation. Methods: Farnesyltranferase activity was determined by Farnesyltranferase [³H] SPA enzyme assay. 𝛃-subunit Farnesyltranferase protein expression was investigated by Western blotting and its mRNA by reverse transcriptase-polymerase chain reaction. K-ras mutation was detected by polymerase chain reaction amplification and restriction enzyme analysis. Multiple linear regression analysis was used to analyse relationships among age, sex, site of tumour. Duke's stage, histological differentiation, K-ras mutation and Farnesyltranferase activity in normal mucosa and cancer. Results: The levels of Farnesyltranferase activity and 𝛃-subunit Farnesyltranferase protein expression were significantly higher in cancer than in normal mucosa. Moreover, tumours located on the right side, with mucinous histological differentiation and with K-ras mutation showed higher levels of Farnesyltranferase use activity. Conclusions: Our findings suggest that Farnesyltranferase activity may be a potential marker of tumourigenicity. The differences in Farnesyltranferase activity in relation to histological grading, tumour location and K-ras mutation described here may constitute a starting point for investigating the causes of this variation within the large bowel.