Scientists have discovered a new approach to decrease Ras membrane association in hepatocellular carcinoma.
Ras proteins (HRas, KRas and NRas) are small GTPases and key regulators of diverse signal transduction pathways controlling cell growth, differentiation and apoptosis. They are common oncogenes that require membrane association for activation. Upregulation of Ras via its overexpression and the downregulation of physiological inhibitors of Ras has been observed in various cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide and the primary cause of death in patients with liver cirrhosis. Previous approaches to block or inhibit Ras membrane association were unsuccessful for cancer treatment in human clinical studies.
A study led by Dr. Ira Kurtz at the Geffen School of Medicine, University of California in Los Angeles observed that the expression of enzyme aminoacylase 3 (AA3) was significantly elevated in the livers of HCC patients and HCC cell lines. Treatment of HepG2 cells with AA3 inhibitors and HepG2 and HuH7 with AA3 siRNA significantly decreased Ras membrane association and was toxic to these HCC cell lines. AA3 inhibitors also increased the levels of N-acetylfarnesylcysteine (NAFC) and N-acetylgeranylgeranylcysteine (NAGGC) in HepG2 and Huh7 cell lines.
The results from this study suggest that AA3 inhibition may be an effective approach in the therapy of HCC and that elevated AA3 expression in HCC is potentially an important diagnostic marker.