Department of Pathology, University of Alabama at Birmingham, 701 S. 19th Street, Birmingham, AL 35294, USA.
Carcinogenesis. 2011 Aug;32(8):1251-8. doi: 10.1093/carcin/bgr092. Epub 2011 May 17.
Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G(1) and G(2) phases. Stearate also increases cell cycle inhibitor p21(CIP1/WAF1) and p27(KIP1) levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras- guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21(CIP1/WAF1) upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27(KIP1), providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo.
先前的研究表明，硬脂酸（C18:0），一种膳食长链饱和脂肪酸，可抑制乳腺癌细胞的恶性进展；然而，调控这些过程的机制却鲜为人知。我们的研究表明，硬脂酸在生理浓度下可抑制人乳腺癌细胞在 G1 和 G2 期的细胞周期进程。硬脂酸还增加细胞周期抑制剂 p21（CIP1/WAF1）和 p27（KIP1）的水平，并同时降低细胞周期依赖性激酶 2（Cdk2）的磷酸化。我们的数据还表明，硬脂酸诱导 Ras-鸟苷三磷酸形成，并导致细胞外信号调节激酶（pERK）的磷酸化增加。MEK1 抑制剂 PD98059 逆转了硬脂酸诱导的 p21（CIP1/WAF1）上调，但仅部分恢复了硬脂酸诱导的 Cdk2 去磷酸化。Ras/丝裂原活化蛋白激酶/ERK 途径与细胞周期调控有关，但通常是正向的。有趣的是，我们发现硬脂酸在体外抑制 Rho 的激活和表达。此外，组成型激活的 RhoC 逆转了硬脂酸诱导的 p27（KIP1）上调，进一步证明了 Rho 的参与。为了在体内测试硬脂酸的效果，我们使用了 N-亚硝基-N-甲基脲大鼠乳腺癌致癌物模型。我们发现，膳食硬脂酸降低了致癌物诱导的乳腺癌的发生率，并降低了肿瘤负担。重要的是，与低脂饮食相比，硬脂酸饮食的大鼠乳腺肿瘤细胞中 RhoA 和 B 以及总 Rho 的表达减少。总的来说，这些数据表明，硬脂酸通过在体外和体内抑制细胞周期中的关键检查点以及 Rho 表达来抑制乳腺癌细胞增殖，并抑制肿瘤负担和致癌物诱导的体内乳腺癌。
