Modulation of the mevalonate pathway and cell growth by linalool in hepatocellular carcinoma cells

RODENAK-KLADNIEW BORIS; GALLE M; CASTRO A; MONTERO VILLEGAS S; DE SAEGER C; STÄRKEL P; CRESPO R; POLO M; GARCIA MARGARITA

Puerto Iguazú

Conferencia; 56th International Conference on the Bioscience of Lipids; 2015

ICBL

Linalool (LN) is a monoterpene - 10 carbons isoprenoid - found in essential oils of many aromatic plants. The mevalonate pathway (MP) has been reported as a branched metabolic pathway modulated by isoprenoids. In addition to cholesterol, this pathway provides several other molecules relevant to cellular metabolism, such as farnesyl pyrophosphate and geranyl?geranyl pyrophosphate, essential in the prenylation of small GTPase Ras, a membrane anchored protein which plays a critical role in survival and cell proliferation. The rate-limiting enzyme of the MP is 3-hydroxy-3-methylglutarylcoenzyme-A reductase (HMGCR). We have previously demonstrated that LN is able to inhibit cell growth and cholesterogenesis in human hepatocellular carcinoma (HepG2) cells, the later as a consequence of the inhibition exerted by linalool at HMGCR level and subsequent steps specifically commmited to cholesterol synthesis. The aim of this work was to elucidate the mechanisms involved in the antiproliferative effects exerted by LN in HepG2 cells. For this purpose cell viabiity and proliferation (WST-1 and BrdU incorporation), apoptosis (TUNEL, caspase-3 activity), cell cycle analysis (flow cytometry), exogenous mevalonate adition and Ras subcellular localization were studied. Our results showed that LN arrested cell cycle progression in G0/G1 phase, induced apoptosis and diminished Ras levels in the membrane fraction. Added exogenous mevalonate failed to reverse the inhibition of proliferation exerted by LN, proposing that HMGCR inhibition alone is not responsible for the antiproliferative activity of this compound and suggesting that Ras inhibition could be responsible, at least in part, for the antiproliferative activity promoted by LN. This inhibition could trigger the G0/G1 arrest and the induction of apoptosis. This work contributes to a clearer understanding of the mechanisms of action of LN suggesting that its use could provide significant health benefits as a chemopreventive and/or chemotherapeutic agent.