Suppression in Mevalonate Synthesis Mediates Antitumor Effects of Combined Statin and γ-Tocotrienol Treatment
Suppression in Mevalonate Synthesis Mediates Antitumor Effects of Combined Statin and γ-Tocotrienol Treatment
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甲羟戊酸合成的抑制介导他汀类药物和 γ-生育三烯酚联合治疗的抗肿瘤作用
作者：
V. Wali;Sunitha V. Bachawal;P. Sylvester
他汀类药物直接抑制3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）活性，而维生素E的同型γ-生育三烯醇（γ-tocotrienol）可增强各种肿瘤细胞系中HMGR的降解并降低其细胞水平。由于单独使用他汀类药物或γ-生育三烯醇可诱导剂量反应性抑制，而联合使用这些药物的次有效剂量可协同抑制+SA乳腺肿瘤细胞的生长，因此本研究旨在探讨HMGR通路在介导低剂量他汀类药物和γ-生育三烯醇联合使用的抗增殖作用中的作用。8 μM辛伐他汀抑制细胞生长和Rap1A和Rab6的异戊二烯化，补充2 μM甲羟戊酸逆转了这些作用。然而，4 μM γ-生育三烯醇的生长抑制作用并不依赖于抑制甲羟戊酸的合成。亚有效剂量的辛伐他汀（0.25 μM）、洛伐他汀（0.25 μM）、美伐他汀（0.25 μM）、普伐他汀（10 μM）或γ-生育三烯醇（2 μM）单独治疗对+SA细胞生长无影响，而这些药物联合治疗可显著抑制+SA细胞生长，并相应降低总HMGR、Rap1A和Rab6烯酰化和MAPK信号，甲羟戊酸补充可逆转这些作用。这些发现表明，低剂量他汀和γ-生育三烯醇联合治疗的协同抗增殖作用与抑制HMGR活性和随后抑制甲羟戊酸合成直接相关。
Statins directly inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, while γ-tocotrienol, an isoform of vitamin E, enhances the degradation and reduces cellular levels of HMGR in various tumor cell lines. Since treatment with statins or γ-tocotrienol alone induced a dose-responsive inhibition, whereas combined treatment with subeffective doses of these agents resulted in a synergistic inhibition in +SA mammary tumor cell growth, studies were conducted to investigate the role of the HMGR pathway in mediating the antiproliferative effects of combined low dose statin and γ-tocotrienol. Treatment with 8 μM simvastatin inhibited cell growth and isoprenylation of Rap1A and Rab6, and supplementation with 2 μM mevalonate reversed these effects. However, the growth inhibitory effects of 4 μM γ-tocotrienol were not dependent upon suppression in mevalonate synthesis. Treatment with subeffective doses of simvastatin (0.25 μM), lovastatin (0.25 μM), mevastatin (0.25 μM), pravastatin (10 μM), or γ-tocotrienol (2 μM) alone had no effect on protein prenylation or mitogenic signaling, whereas combined treatment with these agents resulted in a significant inhibition in +SA cell growth, and a corresponding decrease in total HMGR, Rap1A and Rab6 prenylation, and MAPK signaling, and mevalonate supplementation reversed these effects. These findings demonstrate that the synergistic antiproliferative effects of combined low dose statin and γ-tocotrienol treatment are directly related to an inhibition in HMGR activity and subsequent suppression in mevalonate synthesis.
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DOI：
--
发表时间：
1992-07
期刊：
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
影响因子：
--
作者：
R. Khosravi‐Far;A. Cox;K. Kato;C. Der
通讯作者：
R. Khosravi‐Far;A. Cox;K. Kato;C. Der
DOI：
10.1016/s0021-9258(18)68397-8
发表时间：
1988-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Nakanishi;J. Goldstein;Michael S. Brown
通讯作者：
M. Nakanishi;J. Goldstein;Michael S. Brown
表皮生长因子诱导的小鼠乳腺上皮细胞体外增殖的脂肪酸调节。
影响因子：
3.7
作者：
Sylvester,PW;Birkenfeld,HP;Hosick,HL;Briski,KP
通讯作者：
Briski,KP
影响因子：
11.2
作者：
Campbell, Michael J.;Esserman, Laura J.;Benz, Christopher C.
通讯作者：
Benz, Christopher C.
DOI：
10.1073/pnas.89.14.6403
发表时间：
1992-07-15
影响因子：
11.1
作者：
KATO, K;COX, AD;DER, CJ
通讯作者：
DER, CJ