All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor β to stimulate apoptosis in MCF-7 breast cancer cells
All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor β to stimulate apoptosis in MCF-7 breast cancer cells
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DOI：
10.1677/joe.1.05497
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发表时间：
2004-11-01
影响因子：
4
通讯作者：
Danforth, DN
中科院分区：
文献类型：
--
作者：
Danforth, DN
抗雌激素的4-羟基他莫昔芬()和维生素A相关化合物，维甲酸，在体外和体内协同抑制乳腺癌细胞的生长。为了阐明这种协同作用的机制，我们在体外研究了和全反式维甲酸(AT)对乳腺癌细胞MCF7增殖的影响。和AT具有协同作用，呈时间和剂量依赖性抑制MCF-7细胞的生长。+AT以时间依赖的方式协同作用，下调Bcl2mRNA和Bcl2蛋白的表达，并刺激细胞凋亡。和AT均阻断细胞周期进程，但对此过程无协同或相加作用，提示对细胞凋亡具有选择性协同作用。负生长因子转化生长因子β(TGFβ)是由这些细胞分泌的，并被研究为+AT协同作用的潜在介导者。在72 h内，+AT协同作用使TGFbeta1分泌增加5倍，TGFbeta1单独作用对细胞无凋亡作用，但TGFbeta1联合AT可协同抑制细胞生长，下调Bcl2mRNA和Bcl2蛋白表达，刺激细胞凋亡，其作用与+AT相当。+AT和TGFbeta1+AT对细胞凋亡的协同作用均被雌二醇抑制。+AT与抗TGFβ抗体共同孵育不能阻断Bcl2蛋白表达的下调或对细胞凋亡的刺激。因此，+AT对细胞凋亡的协同作用不依赖于TGFbeta，尽管TGFbeta可能以一种新的方式与AT相互作用，为乳腺癌细胞提供另一种重要的抗增殖机制。
The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throuhout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis.The negative growth factor-transforming growth factor beta (TGFbeta) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGFbeta1 secretion over 72 h. TGFbeta1 alone had no apoptotic effects on these cells; however, TGFbeta1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGFbeta1 +AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGFbeta antibody did not block downregulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGFbeta, although TGFbeta may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.