Exploring Geranylgeraniol and Its Analogues for Targeted Modulation of Lipid Metabolism in Hepatocellular Carcinoma: A Key to Unlocking the Anticancer Efficacy of Statins?

• Grant number: 25/03133-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 01, 2025
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Alejandro Miguel Katzin
• Grantee: Ignasi Bofill Verdaguer
• Supervisor: Jose Carlos Fernandez-Checa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain
• Associated to the scholarship: 22/09526-4 - Inhibition of the polyprenol kinase enzyme of malaria parasites, BP.PD

Abstract

In animals, the mevalonate (MVA) pathway is the primary source of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The MVA pathway is crucial for cholesterol biosynthesis and the prenylation of Ras and Rho oncoproteins, besides several other processes. Therefore, dysregulation of the MVA pathway is associated with hypercholesterolemia, oncogenesis, and other metabolic diseases. Consequently, inhibitors of isoprenoid biosynthesis, such as statins, are routinely used to treat dyslipidemias and have been extensively investigated as anticancer agents, though with limited success in this latter purpose. Regarding this, it has been discovered that dietary geranylgeraniol (GGOH) can be phosphorylated to GGPP and thus bypass the MVA pathway, and possibly rescuing cancerous cells from isoprenoid inhibitors. Paradoxically, GGOH acts as a cellular signal indicating the fulfillment of isoprenoid demands and promotes proteolysis of the MVA enzyme hydroxymethylglutaryl-CoA reductase (HGMR) and a reduction on isoprenoid biosynthesis. In this context, it is plausible that GGOH antimetabolites could enhance the effect of statins, preventing GGOH from acting as an antagonist to the cytotoxic effects of statins and possibly making GGOH itself more cytotoxic to cancer cells. Considering this, we explored the effects of geranylgeranylacetone (GGA) and GGOH on HepG2 hepatocellular carcinoma cells, known for their susceptibility to statins. In vitro studies revealed that GGA has the capacity interfere on [1-(n)-3H] GGOH metabolization and incorporation into cell proteins; enhance the cytotoxic effect of GGOH and simvastatin; and maintain simvastatin cytotoxicity under the presence of GGOH. Furthermore, both GGOH and GGA demonstrated to dysregulate the incorporation of [1-14C] acetate into lipids, especially when cells are simultaneously exposed to both diterpenes. Our results suggest the repositioning of GGA combined with statins for the treatment of hepatocellular carcinoma and exploring this combination against other types of malignancies. Furthermore, our study reveals GGOH as an endogenous compound capable of regulating several metabolic processes. Considering this, we are presenting a proposal for the Postdoctoral Research Internships Abroad Program to deepen our understanding of the regulatory mechanisms of geranylgeranylacetone (GGA) and geranylgeraniol (GGOH) in carbon metabolism. This research aims to elucidate the roles these compounds play in metabolic pathways and to explore their potential therapeutic applications in managing dyslipidemias and treating cancer. By investigating the molecular interactions and downstream effects of GGA and GGOH, we hope to uncover insights that could inform innovative strategies for disease treatment and metabolic regulation.