Mevalonate pathway intermediates downregulate zoledronic acid- induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells

Johanna Räikkönen , Hannu Mönkkönen , Seppo Auriola , Jukka Mönkkönen

Increasing evidence is accumulating that zoledronic acid (ZOL), a nitrogen-containing bisphosphonate (N-BP), is able to affect tumor cells by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). The consequent accumulation of unprenylated proteins is believed to largely account for the cytotoxic effects of ZOL. FPPS inhibition leads also to the accumulation of isopentenyl pyrophosphate (IPP) and the apoptotic ATP analog, ApppI, but the role of this mechanism in the cytotoxic action of bisphosphonates is less clear. Since treatment with MVP intermediates has been shown to overcome N-BP-induced apoptosis via rescuing protein prenylation, our aim here was to determine their mechanism of action on ZOL-induced IPP/ApppI accumulation.

Mots clés: AppCClp; ApppI; ApppD; BP; CLOD; DMAPP; ESI; FOH; FPP; GGOH; GGPP; HMGR; IPP; MS; MVP; ZOL; Bisphosphonate-induced ATP analog; Isopentenyl pyrophosphate; Isoprenoid; Mevalonate pathway; 3-hydroxy-3-methylglutaryl-coenzyme A; Zoledronic acid

Johanna Räikkönen, Hannu Mönkkönen, Seppo Auriola, Jukka Mönkkönen. Mevalonate pathway intermediates downregulate zoledronic acid- induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells. Biochemical Pharmacology, 2009, 79 (5), pp.777. ⟨10.1016/j.bcp.2009.10.003⟩. ⟨hal-00547635⟩