Role for protein geranylgeranylation in adult T-cell leukemia cell survival

Nonaka, Mizuho; Uota, Shin; Saitoh, Yasunori; Takáhashi, Mayumí; Sugimoto, Hitoshi; Amet, Tohti; Arai, Ayako; Miura, Osamu; Yamamoto, Naoki; Shoji, Yasuhiro

doi:10.1016/j.yexcr.2008.10.010

Cited by 26 publications

(26 citation statements)

References 53 publications

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“…Geranylgeranylation of Rho GTPase ensures membrane localization and activation (74) that can be affected by statins, small-molecule inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins modulate lipid metabolism and geranylgeranylation of Rho GTPase (58,73) and induce apoptosis and inhibit proliferation in various cancer cell lines and human smooth muscle cells (22,23,48,66,71,84,91). Importantly, statins synergize with rapamycin and its analogs in inhibiting proliferation and inducing apoptosis in leukemia, prostate and breast cancer, and rat smooth muscle cells (6,8,17,70).…”

mentioning

confidence: 99%

mTORC2 Is Required for Proliferation and Survival of TSC2-Null Cells

Goncharova

Goncharov

et al. 2011

Molecular and Cellular Biology

107

129

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Mutational inactivation of the tumor suppressor tuberous sclerosis complex 2 (TSC2) constitutively activates mTORC1, increases cell proliferation, and induces the pathological manifestations observed in tuberous sclerosis (TS) and in pulmonary lymphangioleiomyomatosis (LAM). While the role of mTORC1 in TSC2-dependent growth has been extensively characterized, little is known about the role of mTORC2. Our data demonstrate that mTORC2 modulates TSC2-null cell proliferation and survival through RhoA GTPase and Bcl2 proteins. TSC2-null cell proliferation was inhibited not only by reexpression of TSC2 or small interfering RNA (siRNA)-induced downregulation of Rheb, mTOR, or raptor, but also by siRNA for rictor. Increased RhoA GTPase activity and P-Ser473 Akt were inhibited by siRNA for rictor. Importantly, constitutively active V14RhoA reversed growth inhibition induced by siRNA for rictor, siRNA TSC1, reexpression of TSC2, or simvastatin. While siRNA for RhoA had a modest effect on growth inhibition, downregulation of RhoA markedly increased TSC2-null cell apoptosis. Inhibition of RhoA activity downregulated antiapoptotic Bcl2 and upregulated proapoptotic Bim, Bok, and Puma. In vitro and in vivo, simvastatin alone or in combination with rapamycin inhibited cell growth and induced TSC2-null cell apoptosis, abrogated TSC2-null tumor growth, improved animal survival, and prevented tumor recurrence by inhibiting cell growth and promoting apoptosis. Our data demonstrate that mTORC2-dependent activation of RhoA is required for TSC2-null cell growth and survival and suggest that targeting both mTORC2 and mTORC1 by a combination of proapoptotic simvastatin and cytostatic rapamycin shows promise for combinational therapeutic intervention in diseases with TSC2 dysfunction.

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mentioning

confidence: 99%

mTORC2 Is Required for Proliferation and Survival of TSC2-Null Cells

Goncharova

Goncharov

et al. 2011

Molecular and Cellular Biology

107

129

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“…Members of Rho and Ras family are known to have a key role in regulating cell shape and motility or secretion and proliferation, respectively. 30,[33][34][35] Thus, the effects of fluvastatin reported here may be dependent on the decrease of cell membrane cholesterol content and/or on the inhibition of small GTP-binding proteins. Our present data suggest that fluvastatin treatment inhibits the immunosuppressive effect of BMSC by interfering with the isoprenylation and activation of GTP-binding proteins.…”

Section: Discussionmentioning

confidence: 80%

Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival

Musso¹,

Zocchi

Poggi

2010

Haematologica

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“…(Kornblau et al, 2007) Statins are pharmacologic inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) -the regulatory enzyme of CH synthesis (Nonaka et al, 2009;Sassano et al, 2007). In vitro, they block HMG-CoA reductase and by this they contribute to restore sensitivity to chemotherapy.…”

Section: Statins As Adjuvant Treatment In Malignant Hemopathiesmentioning

confidence: 99%

“…(Kornblau et al, 2007) HMG-CoA regulates not only the synthesis of CH but also that of the higher isoprenoids, as geranylgeranyl pyrophosphate (Fuchs et al, 2008). By the inhibition of the prenylation processes, in vitro, statins reduce cellular proliferation and stimulate apoptosis of cancerous cells (Nonaka et al, 2009;Sassano et al, 2007). It was found that simvastatin inhibits geranylgeranylation processes of small GTPases Rab5B and Rac1 in certain leukemic cells (for example, adult T-cell leukemia).…”

Section: Statins As Adjuvant Treatment In Malignant Hemopathiesmentioning

confidence: 99%

“…It was found that simvastatin inhibits geranylgeranylation processes of small GTPases Rab5B and Rac1 in certain leukemic cells (for example, adult T-cell leukemia). (Nonaka et al, 2009) The excessive proliferation inhibition induced by simvastatin results from the induction of apoptosis, cell cycle arrest in phase G2 / M, and accumulation of p21 protein. Simvastatin is able to remove resistance to apoptosis that occurs during treatment with bortezomib, by reducing geranylgeranyl pyrophosphate synthesis and cell survival mechanism dependant on this.…”

Section: Statins As Adjuvant Treatment In Malignant Hemopathiesmentioning

confidence: 99%

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