REVERSION OF TRANSFORMED PHENOTYPE OF HUMAN ADENOCARCINOMA A549 CELLSBY EXPRESSION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE COMPLEMENTARY-DNA

3-Hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) plays a r ate-limiting role in isoprenoid biosynthesis and is associated with ce ll proliferation and transformation. Although an elevated level of HMG -CoA reductase activity is consistently detected in cancer cell lines and tumors, the question remains whether HMG-CoA reductase activity ma y have a causative role in cell transformation. We have stably transfe cted the A549 human adenocarcinoma cells with both bicistronic and ret roviral expression vectors, including the whole cDNA of human HMG-CoA reductase. Stably transfected cells showed strong morphological change s and disorganization in the filamentous actin architecture, became co ntact inhibited, and had a lower doubling time; Moreover, they exhibit ed anchorage-independent growth reduction and lost their capability to induce tumors in nude mice. Surprisingly, no quantitative modificatio n of enzyme activity was observed following transfection, although exp ression of HMG-CoA reductase cDNA was shown by Northern blot analysis. When endogenous and transfected reductase activity was bypassed by th e addition of mevalonate and compactin, a competitive inhibitor, the f ilamentous actin distribution in HMG-CoA reductase-transfected cells b ecame very similar to that of control cells, demonstrating the role of exogenous HMG-CoA reductase activity in this process. All of our data together strongly suggest that phenotype reversion is dependent on ex ogenous HMG-CoA reductase expression and that enzymatic activity is im plied in this mechanism. HMG-CoA reductase cDNA expression, by express ion of a particular form of reductase, might be a negative regulator o f cell growth and thus reverse the phenotype of tumor cells.