Hypoxia induces proteasome-dependent degradation of estrogen receptor a in ZR-75 breast cancer cells
Hypoxia induces proteasome-dependent degradation of estrogen receptor a in ZR-75 breast cancer cells
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DOI：
10.1210/me.2001-0347
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发表时间：
2002-10-01
影响因子：
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通讯作者：
Safe, S
中科院分区：
文献类型：
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作者：
Stoner, M;Saville, B;Safe, S
雌激素受体α（ER α）的调节在激素反应性和ER阳性乳腺癌细胞和肿瘤的生长中起重要作用。ZR-75乳腺癌细胞在常氧（21%O-2）或缺氧（1%O-2或氯化钴）条件下生长，缺氧显著增加缺氧诱导因子1a蛋白在治疗后3小时内，而ER α蛋白水平显着降低在6-12小时内，这种反应被蛋白酶体抑制剂MG-132阻断。与此相反，缺氧诱导细胞的Sp1蛋白只有最小的减少，并没有影响ER α mRNA，然而，缺氧条件下减少基础和17 β-雌二醇诱导的pS2基因表达（mRNA水平）和雌激素反应元件依赖的ZR-75细胞的报告基因活性。虽然17 β-雌二醇和缺氧诱导ER α的蛋白酶体依赖性降解，但它们对反式激活的影响是不同的，这可能对乳腺肿瘤的临床治疗有意义。
Regulation of estrogen receptor alpha (ERalpha) plays an important role in hormone responsiveness and growth of ER-positive breast cancer cells and tumors. ZR-75 breast cancer cells were grown under conditions of normoxia (21% O-2) or hypoxia (1% O-2 or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1 a protein within 3 h after treatment, whereas ERalpha protein levels were dramatically decreased within 6-12 h, and this response was blocked by the proteasome inhibitor MG-132. In contrast, hypoxia induced only minimal decreases in cellular Sp1 protein and did not affect ERa mRNA; however, hypoxic conditions decreased basal and 17beta-estradiol- induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17beta-estradiol and hypoxia induce proteasome-dependent degradation of ERa, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.