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Bisphosphonates induce autophagy by depleting geranylgeranyl diphosphate
Brian M Wasko1, Amel Dudakovic, Raymond J Hohl
1Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA 52242, USA.
The Journal of Pharmacology and Experimental Therapeutics
|February 22, 2011
Summary
Bisphosphonates induce autophagy by inhibiting isoprenoid biosynthesis, depleting geranylgeranyl diphosphate (GGPP), and impairing protein geranylgeranylation, particularly affecting GGTase II substrates in cancer cells.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
Background:
- Isoprenoid biosynthesis intermediates are linked to autophagy induction.
- The precise mechanism of autophagy induction by isoprenoid biosynthesis inhibitors remains unclear.
Purpose of the Study:
- To investigate if bisphosphonates induce autophagy by inhibiting farnesyl diphosphate synthase (FDPS) and geranylgeranyl diphosphate synthase (GGDPS).
- To determine if depleted geranylgeranyl diphosphate (GGPP) and impaired protein geranylgeranylation mediate this autophagy induction.
Main Methods:
- Utilized PC3 prostate cancer and MDA-MB-231 breast cancer cells.
- Administered FDPS inhibitor (zoledronate) and GGDPS inhibitor (digeranyl bisphosphonate, DGBP).
- Assessed autophagy marker LC3-II accumulation and autophagic flux using protease inhibitors and bafilomycin A1; analyzed protein geranylgeranylation of Rab6 and Rap1a.
Main Results:
- Zoledronate and DGBP induced autophagy, evidenced by LC3-II accumulation and increased autophagic flux.
- Exogenous GGPP reversed LC3-II accumulation and Rab6 geranylgeranylation impairment but not Rap1a geranylgeranylation impairment.
- Specific farnesyl transferase and geranylgeranyl transferase I inhibitors did not induce autophagy.
- Bafilomycin A1 enhanced the antiproliferative effects of DGBP.
Conclusions:
- Bisphosphonates induce autophagy, a finding demonstrated here for the first time.
- Autophagy induction by these agents in PC3 cells likely depends on impaired geranylgeranylation of GGTase II substrates.
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