Hydrophobic statins induce autophagy in cultured human rhabdomyosarcoma cells

Araki, Makoto; Motojima, Kiyoto

doi:10.1016/j.bbrc.2007.12.166

Cited by 58 publications

(55 citation statements)

References 22 publications

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“…autophagy in vitro, 21,22 lending credence to our hypothesis that active autophagy is the potential driving force behind colchicineinduced muscle toxicity. To explore the impact of enhanced autophagy in colchicine-induced myopathy, we evaluated muscle pathology in mice treated with rapamycin or simvastatin in the setting of colchicine.…”

Section: Introductionsupporting

confidence: 58%

“…Previous studies have demonstrated that statins can induce autophagy in cell culture models of skeletal muscle, 21,22 but it has not been established whether this occurs in vivo in mature skeletal muscle. To evaluate this, we treated mice with four different statin drugs (simvastatin, atorvastatin, lovastatin, and pravastatin) for 7 d prior to isolating skeletal muscle and performing an immunoblot using an anti-LC3 antibody.…”

Section: Statins Induce Autophagy In Mouse Skeletal Musclementioning

confidence: 99%

See 1 more Smart Citation

Increased autophagy accelerates colchicine-induced muscle toxicity

Ching¹,

Ju²,

Pittman³

et al. 2013

Autophagy

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Section: Introductionsupporting

confidence: 58%

Section: Statins Induce Autophagy In Mouse Skeletal Musclementioning

confidence: 99%

Increased autophagy accelerates colchicine-induced muscle toxicity

Ching¹,

Ju²,

Pittman³

et al. 2013

Autophagy

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“…However, in HepG2 and MDA-MB-468 cells, LC3-II accumulation was not observed in the presence of lovastatin or bisphosphonates (zoledronate and DGBP). It has been reported previously (Araki and Motojima, 2008) that statins do not induce autophagy in HepG2 cells. These results are not due to a lack of inducible autophagy, as both HepG2 and MDA-MB-468 have been reported to be capable of autophagic induction (Cheng et al, 2010;Wang et al, 2010).…”

Section: Discussionmentioning

confidence: 80%

“…Studies have shown that statins are capable of inducing autophagy in A204 human rhabdomyosarcoma cells (Araki and Motojima, 2008). More recently, statins have been shown to induce autophagy in PC3 prostate cancer cells, and the induction of autophagy was prevented by the addition of the geranylgeraniol, the alcohol form of GGPP (Parikh et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

Wasko¹,

Dudakovic²,

Hohl³

2011

J Pharmacol Exp Ther

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Multiple studies have implicated the depletion of isoprenoid biosynthetic pathway intermediates in the induction of autophagy. However, the exact mechanism by which isoprenoid biosynthesis inhibitors induce autophagy has not been well established. We hypothesized that inhibition of farnesyl diphosphate synthase (FDPS) and geranylgeranyl diphosphate synthase (GGDPS) by bisphosphonates would induce autophagy by depleting cellular geranylgeranyl diphosphate (GGPP) and impairing protein geranylgeranylation. Herein, we show that an inhibitor of FDPS (zoledronate) and an inhibitor of GGDPS (digeranyl bisphosphonate, DGBP) induce autophagy in PC3 prostate cancer and MDA-MB-231 breast cancer cells as measured by accumulation of the autophagic marker LC3-II. Treatment of cells with lysosomal protease inhibitors [(2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester (E-64d) and pepstatin A] in combination with zoledronate or digeranyl bisphosphonate further enhances the formation of LC3-II, indicating that these compounds induce autophagic flux. It is noteworthy that the addition of exogenous GGPP prevented the accumulation of LC3-II and impairment of Rab6 (a GGTase II substrate) geranylgeranylation by isoprenoid pathway inhibitors (lovastatin, zoledronate, and DGBP). However, exogenous GGPP did not restore isoprenoid pathway inhibitorinduced impairment of Rap1a (a GGTase I substrate) geranylgeranylation. In addition, specific inhibitors of farnesyl transferase and geranylgeranyl transferase I are unable to induce autophagy in our system. Furthermore, the addition of bafilomycin A1 (an inhibitor of autophagy processing) enhanced the antiproliferative effects of digeranyl bisphosphonate. These results are the first to demonstrate that bisphosphonates induce autophagy. Our study suggests that induction of autophagy in PC3 cells with these agents is probably dependent upon impairment of geranylgeranylation of GGTase II substrates.

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“…Recently, three FTIs were found to induce autophagy in two different human cancer cell lines (Pan et al, 2008). In addition, some statins can induce autophagy in a cell type-specific manner owing to their ability to inhibit protein prenylation rather than cholesterol synthesis (Araki and Motojima, 2008). For instance, cerivastatin or simvastatin are capable of inducing autophagy in rhabdomyosarcoma cells (Araki and Motojima, 2008), whereas lovastatin or simvastatin fail to do so in hepatocytes (Samari and Seglen, 1998).…”

Section: Discussionmentioning

confidence: 99%

A Novel Geranylgeranyl Transferase Inhibitor in Combination with Lovastatin Inhibits Proliferation and Induces Autophagy in STS-26T MPNST Cells

Sane

Mynderse

LaLonde

et al. 2010

J Pharmacol Exp Ther

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Prenylation inhibitors have gained increasing attention as potential therapeutics for cancer. Initial work focused on inhibitors of farnesylation , but more recently geranylgeranyl transferase inhibitors (GGTIs) have begun to be evaluated for their potential antitumor activity in vitro and in vivo. In this study, we have developed a nonpeptidomimetic GGTI, termed GGTI-2Z [(5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate], which in combination with lovastatin inhibits geranylgeranyl transferase I (GGTase I) and GGTase II/RabGGTase, without affecting farnesylation. The combination treatment results in a G 0 /G 1 arrest and synergistic inhibition of proliferation of cultured STS-26T malignant peripheral nerve sheath tumor cells. We also show that the antiproliferative activity of drugs in combination occurs in the context of autophagy. The combination treatment also induces autophagy in the MCF10.DCIS model of human breast ductal carcinoma in situ and in 1c1c7 murine hepatoma cells, where it also reduces proliferation. At the same time, there is no detectable toxicity in normal immortalized Schwann cells. These studies establish GGTI-2Z as a novel geranylgeranyl pyrophosphate derivative that may work through a new mechanism involving the induction of autophagy and, in combination with lovastatin, may serve as a valuable paradigm for developing more effective strategies in this class of antitumor therapeutics.Lipid modifications of proteins are known to facilitate their membrane association, cellular localization, and protein-protein interactions, which are related to their functions including cell survival, proliferation, differentiation, and invasion. Most GTPases, like Ras, contain a C-terminal CaaX motif that undergoes prenylation catalyzed by prenyl transferase enzymes, including farnesyl transferase (FTase) or geranylgeranyl transferase I (GGTase I), followed by serial modification via several other enzymes (Konstantinopoulos et al., 2007). The substrate specificities of FTase and GGTase I are not mutually exclusive and, therefore, cross-prenylation can

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Hydrophobic statins induce autophagy in cultured human rhabdomyosarcoma cells

Cited by 58 publications

References 22 publications

Increased autophagy accelerates colchicine-induced muscle toxicity

Increased autophagy accelerates colchicine-induced muscle toxicity

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

A Novel Geranylgeranyl Transferase Inhibitor in Combination with Lovastatin Inhibits Proliferation and Induces Autophagy in STS-26T MPNST Cells

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