Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells

Xia, Zhenlei; Tan, MM; Wong, Wendy Wei-Lynn; Dimitroulakos, Jim; Minden,; Penn, Linda Z.

doi:10.1038/sj.leu.2402196

Cited by 190 publications

(165 citation statements)

References 41 publications

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“…As isopentenyl PPi is also depleted by statin exposure, it would be unavailable to the statin-treated cell (49,50). These results, as well as the ability of GGTI-298 to induce apoptosis comparably with statins in sensitive tumor lines, build on previous reports (1,11,16,41) to clearly indicate the importance of protein geranylgeranylation in statininduced apoptosis.…”

Section: Discussionsupporting

confidence: 83%

“…We and others have shown that of these downstream end-products, GGPP most consistently reverses statin-induced apoptosis in sensitive tumor cells (1,11,16,41). To evaluate the mechanism of lovastatininduced apoptosis in MM, four sensitive MM cell lines (KMS11, OPM2, H929 and OCI MY7) were screened by 3-4,5-dimethylthiazolyl-2,2,5-diphenyl tetrazolium bromide assay, as we have previously conducted (41).…”

Section: Mevalonate and Ggpp Abrogate Lovastatin-induced Apoptosis Inmentioning

confidence: 99%

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Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Wong

Clendening

Martirosyan

et al. 2007

Molecular Cancer Therapeutics

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Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (P = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM. [Mol Cancer Ther 2007;6(6):1886 -97]

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Section: Discussionsupporting

confidence: 83%

Section: Mevalonate and Ggpp Abrogate Lovastatin-induced Apoptosis Inmentioning

confidence: 99%

Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Wong

Clendening

Martirosyan

et al. 2007

Molecular Cancer Therapeutics

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“…We cannot rule out the possibility that, in addition to RhoA, other geranylgeranylated proteins are involved, because it is estimated that 0.5-1% of all cellular proteins are geranylgeranylated (37). Furthermore, we showed that the expression of Rock-2 was not reduced in fluvastatintreated RA synovial cells.…”

Section: Discussionmentioning

confidence: 69%

Apoptosis of rheumatoid synovial cells by statins through the blocking of protein geranylgeranylation: A potential therapeutic approach to rheumatoid arthritis

Nagashima¹,

Okazaki²,

Yudoh³

et al. 2006

Arthritis & Rheumatism

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Objective. To determine whether statins induce apoptosis in rheumatoid arthritis (RA) synoviocytes.Methods. The effects of lipophilic and hydrophilic statins (fluvastatin and pravastatin, respectively) on the apoptosis of cultured RA synoviocytes were examined in vitro. Apoptosis was analyzed by flow cytometry after staining with JC-1 (to measure the mitochondrial transmembrane potential), active caspase 3, annexin V, and propidium iodide. Add-back experiments were conducted to determine which downstream products of the mevalonate pathway could suppress apoptosis. Modulation of various signaling pathways induced by statins, including protein prenylation, was also investigated.Results. Fluvastatin, but not pravastatin, induced apoptosis in RA synoviocytes in a concentrationdependent (1-10 M) and time-dependent (48-96 hours) manner. Another lipophilic statin, pitavastatin, displayed almost the same effects as fluvastatin. In sharp contrast, lipophilic statins did not significantly increase apoptosis in synoviocytes from patients with osteoarthropathy. Apoptosis induced by fluvastatin was mitochondrial-and caspase 3-dependent and was abrogated by mevalonate and geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate. In addition, the geranylgeranyl transferase inhibitor GGTI-298 mimicked the effect of fluvastatin on RA synoviocytes. Treatment of RA synoviocytes with the RhoA kinase inhibitor Y-27632 caused apoptosis. Fluvastatin decreased the amount of RhoA protein in the membrane fraction, but increased the amount in the cytosolic fraction.Conclusion. Fluvastatin induced apoptosis in RA synoviocytes through a mitochondrial-and caspase 3-dependent pathway and by the blockage of mevalonate pathways, particularly through the inhibition of protein geranylgeranylation and RhoA/RhoA kinase pathways. These findings suggest that lipophilic statins have potential as novel therapeutic agents for RA.

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“…3 The isoprenylation of Ras proteins is critical for their cellular function and inhibition of isoprenylation abolishes the transforming activity of mutated Ras proteins. 4 Lovastatin, one of the statins that has also been found to arrest tumor and normal cells in G1 phase of the cell cycle, 5,6 induced a potent apoptotic response [7][8][9][10] and has been demonstrated to exert antitumor effects in mice. [11][12][13][14][15] In several studies using murine melanoma models, lovastatin was shown to have antitumor effects both when used alone 12 or in combination with other agents.…”

mentioning

confidence: 99%

Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis‐dependent mechanism

Feleszko

Młynarczuk

Olszewska

et al. 2002

Intl Journal of Cancer

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Lovastatin, a drug successfully used in the clinic to prevent and to treat coronary heart disease, has recently been reported to decrease the incidence of melanoma in lovastatintreated patients. Lovastatin has also been proved to potentiate antitumor effects of both cisplatin and TNF-␣ in murine melanoma models. Recently, an augmented therapeutic effect of lovastatin and doxorubicin has been reported in 3 tumor models in mice. In our preliminary study lovastatin caused retardation of melanoma growth in mice treated with doxorubicin (Feleszko et al. J Natl Cancer Inst 1998;90:247-8). In the present report, we supplement our preliminary observations and demonstrate in 2 murine and 2 human melanoma cell lines that lovastatin effectively potentiates the cytostatic/cytotoxic activity of doxorubicin in vitro via an augmentation of apoptosis (estimated with PARP-cleavage assay, annexin V assay and TUNEL) . The combined antiproliferative activity of lovastatin and doxorubicin was evaluated using the combination index (CI) method of Chou and Talalay, revealing synergistic interactions in melanoma cells exposed to lovastatin and doxorubicin. In B16F10 murine melanoma model in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (5 mg/kg for 14 days) and doxorubicin (4 ؋ 1 mg/kg) as compared with either agent acting alone. Lovastatin treatment resulted also in significant reduction of the number of experimental metastasis in doxorubicin-treated mice. The results of our studies suggest that lovastatin may enhance the effectiveness of chemotherapeutic agents in the treatment of malignant melanomas.

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Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells

Cited by 190 publications

References 41 publications

Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

Apoptosis of rheumatoid synovial cells by statins through the blocking of protein geranylgeranylation: A potential therapeutic approach to rheumatoid arthritis

Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis‐dependent mechanism

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