Inhibition of Geranylgeranyl Pyrophosphate Synthase Results in Altered Small GTPase mRNA Levels in Multiple Myeloma

Growth of malignant cells is partially regulated by small GTPases that are post‐translationally modified by addition of a twenty‐carbon geranylgeranyl moiety. Among the drugs that are used clinically that inhibit the modification and signaling of small GTPases are bisphosphonates, which inhibit farnesyl diphosphate synthase and deplete cells of downstream isoprenoids including geranylgeranyl pyrophosphate (GGPP). We have designed a series of novel bisphosphonates, including digeranyl bisphosphonate[1], which inhibit GGPP synthase. Through the use of quantitative PCR, we investigated the mRNA levels of all small GTPase substrates of geranylgeranyl transferase type I (GGTase I) in RPMI‐8226 multiple myeloma cells upon depletion of GGPP with digeranyl bisphosphonate. The results show that GGPP depletion significantly increases mRNA levels of a select group of GGTase I substrate GTPases, including K‐Ras, RhoB, and Rnd3. The majority of GGTase I substrates are relatively unchanged by GGPP depletion. These results show for the first time that cellular inhibition of GGPP synthase leads to up regulation of specific key genes. Research Support: This project was supported by the Roy. J. Carver Charitable Trust as a Research Program of Excellence and the Roland W. Holden Family Program for Experimental Cancer Therapeutics.