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. 2020 Feb 12;117(8):4158–4168. doi: 10.1073/pnas.1917938117

Fig. 3.

Fig. 3.

Modulation of geranylgeranylation mediates the cytotoxic effects of pitavastatin. (A) Schematic of the mevalonate pathway. Chemical inhibitors of specific steps are in orange. (B) The addition of Mev or geranylgeranyl pyrophosphate (GGPP) rescues pitavastatin-induced cell death in Dictyostelium pten− cells. Images were taken 72 h after drug addition. (Scale bar, 20 μm.) (C) The addition of Mev rescues pitavastatin-induced cell death in MCF10A PTEN−/− cells. Images were taken 68 h after drug addition. (Scale bar, 30 μm.) (D) Measurement of MCF10A and PTEN−/− cell growth in the absence or presence of Mev and increasing concentrations of pitavastatin (mean ± SD, n = 3). (E) Inhibition of geranylgeranyl transferase (with GGTI, 48 h), but not squalene synthase (with YM, 68 h) or farnesyl transferase (with FTI, 68 h), is able to recapitulate pitavastatin treatment. (Scale bar, 30 μm.) (F) The addition of GGPP or geranyl pyrophosphate rescues pitavastatin-induced cell death. Images were taken 68 h after drug addition. (Scale bar, 30 μm.) (G) Measurement of MCF10A and PTEN−/− cell growth in the absence or presence of GGPP and increasing concentrations of pitavastatin (mean ± SD, n = 3).