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Published on: September 3, 2013
Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells
M Goffinet1, M Thoulouzan, A Pradines
1Inserm U563, Centre de Physiopathologie de Toulouse Purpan, Département Innovation Thérapeutique et Oncologie Moléculaire, Institut Claudius Regaud, Toulouse, France. goffinet@icr.fnclcc.fr
Background:
Nitrogen-containing bisphosphonates (N-BPs) have been designed to inhibit osteoclast-mediated bone resorption. However, it is now accepted that part of their anti-tumor activities is related to interference with the mevalonate pathway.
Methods:
We investigated the effects of zoledronic acid (ZOL), on cell proliferation and protein isoprenylation in two tumoral (LnCAP, PC-3,), and one normal established (PNT1-A) prostatic cell line. To assess if inhibition of geranyl-geranylation by ZOL impairs the biological activity of RhoA GTPase, we studied the LPA-induced formation of stress fibers. The inhibitory effect of ZOL on geranyl geranyl transferase I was checked biochemically. Activity of ZOL on cholesterol biosynthesis was determined by measuring the incorporation of 14C mevalonate in cholesterol.
Results:
ZOL induced dose-dependent inhibition of proliferation of all the three cell lines although it appeared more efficient on the untransformed PNT1A. Whatever the cell line, 20 microM ZOL-induced inhibition was reversed by geranyl-geraniol (GGOH) but neither by farnesol nor mevalonate. After 48 hours treatment of cells with 20 microM ZOL, geranyl-geranylation of Rap1A was abolished whereas farnesylation of HDJ-2 was unaffected. Inhibition of Rap1A geranyl-geranylation by ZOL was rescued by GGOH and not by FOH. Indeed, as observed with treatment by a geranyl-geranyl transferase inhibitor, treatment of PNT1-A cells with 20 microM ZOL prevented the LPA-induced formation of stress fibers. We checked that in vitro ZOL did not inhibit geranyl-geranyl-transferase I. ZOL strongly inhibited cholesterol biosynthesis up to 24 hours but at 48 hours 90% of this biosynthesis was rescued.
Conclusion:
Although zoledronic acid is currently the most efficient bisphosphonate in metastatic prostate cancer management, its mechanism of action in prostatic cells remains unclear. We suggest in this work that although in first intention ZOL inhibits FPPsynthase its main biological actitivity is directed against protein Geranylgeranylation.
Insights
Zoledronic acid (ZOL) inhibits prostate cancer cell proliferation by interfering with protein geranylgeranylation, a key pathway for cell signaling and survival. This finding clarifies ZOL's anti-tumor effects beyond bone resorption.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Nitrogen-containing bisphosphonates (N-BPs) are known to inhibit bone resorption.
- Emerging evidence suggests N-BPs also possess anti-tumor activities by interfering with the mevalonate pathway.
Purpose of the Study:
- To investigate the effects of zoledronic acid (ZOL) on prostate cancer cell proliferation and protein isoprenylation.
- To determine if ZOL's inhibition of geranyl-geranylation impacts RhoA GTPase activity and cellular functions.
Main Methods:
- Assessed ZOL's impact on cell proliferation and protein isoprenylation in prostate cell lines (LnCAP, PC-3, PNT1-A).
- Studied the effect of ZOL on LPA-induced stress fiber formation to evaluate RhoA GTPase activity.
- Biochemically analyzed ZOL's inhibition of geranyl-geranyl transferase I and its effect on cholesterol biosynthesis.
Main Results:
- ZOL dose-dependently inhibited proliferation in all tested cell lines, with greater efficacy in the normal PNT1-A line.
- ZOL treatment abolished geranyl-geranylation of Rap1A, a process reversible by geranyl-geraniol (GGOH).
- ZOL inhibited cholesterol biosynthesis, but this effect was largely rescued after 48 hours.
Conclusions:
- Zoledronic acid's anti-tumor activity in prostate cancer may stem from its interference with protein geranylgeranylation.
- While ZOL may initially inhibit FPP synthase, its primary biological impact in prostate cells is through protein geranylgeranylation.
- Understanding this mechanism can refine therapeutic strategies for metastatic prostate cancer management.
