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. Author manuscript; available in PMC: 2019 Jan 17.
Published in final edited form as: Sci Transl Med. 2018 Jun 13;10(445):eaaq1240. doi: 10.1126/scitranslmed.aaq1240

Figure 4. Sensitization to venetoclax requires inhibition of protein geranylgeranylation.

Figure 4.

A, viability of cells treated with the combination of 300 nM navitoclax and 10 µM simvastatin supplemented with indicated metabolites for 48 hours. Abbreviations are as follows; MVA: mevalonate, FPP: farnesyl pyrophosphate, GGPP: geranylgeranyl pyrophosphate. n = 4 (OCI-LY8 control and GGPP); n = 3 (OCI-LY8 MVA/cholesterol, and all SU-DHL4 groups). B, viability of cells treated as indicated with 10 µM simvastatin, GGTI-298, or FTI-277 with (black bars) or without (white bars) venetoclax (30 nM for OCI-LY8, 300 nM for SU-DHL4) for 48 hours. Viability was assessed by flow cytometry using Annexin-V and PI double-negativity; n = 3 (Sim and FTI), n = 5 or 6 (GGTI and DMSO). C, western blot of cells treated with 10 µM of indicated inhibitors for 16 hours. Statin and FTI-277 but not GGTI-498 caused a mobility shift of HDJ-2 (slower migrating, unprenylated form). Statin and GGTI-498 but not FTI-277 induced the appearance of unprenylated RAP1A. D, dynamic BH3 profile of cells treated with 10 µM simvastatin (blue bars) or GGTI-298 (black bars) for 16 hours; n = 5 (OCI-LY8, DMSO, and Sim), n = 2 (OCI-LY8, GGTI), n = 4 (SU-DHL4, all conditions). Significance testing was performed by two-tailed paired Student’s t-test relative to vehicle-treated control samples in panels A and B, one-tailed in panel D.