Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1.
Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1.
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DOI：
10.1158/1940-6207.capr-12-0201
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Dannenberg AJ
中科院分区：
文献类型：
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作者：
Subbaramaiah K;Howe LR;Zhou XK;Yang P;Hudis CA;Kopelovich L;Dannenberg AJ
雌激素合成由细胞色素 P450 芳香酶催化，该酶由 CYP19 基因编码。在肥胖的绝经后女性中，白色脂肪组织中芳香酶活性的增加被认为会导致激素依赖性乳腺癌。前列腺素 E2 (PGE2) 刺激 cAMP→蛋白激酶 A (PKA) 通路，导致发炎的白色脂肪组织中 CYP19 转录增加和芳香酶活性升高。 15-羟基前列腺素脱氢酶 (15-PGDH) 在 PGE2 的分解代谢中起主要作用。在这里，我们研究了核受体 PPARγ 的配体吡格列酮抑制芳香酶表达的机制。用吡格列酮处理人前脂肪细胞会抑制 Snail（一种抑制性转录因子），导致培养基中 15-PGDH 水平升高，PGE2 水平降低。吡格列酮还抑制 cAMP→PKA 信号传导，导致磷酸化 cAMP 响应元件结合蛋白、p300 和 CYP19 I.3/II 启动子之间的相互作用减少。 BRCA1 是 CYP19 转录的阻遏蛋白，由吡格列酮诱导。与这些体外研究结果一致，用吡格列酮治疗小鼠可激活 PPARγ、诱导 15-PGDH 和 BRCA1，同时抑制乳腺中的芳香酶水平。总的来说，这些结果表明 PPARγ 的激活会诱导 BRCA1 并抑制 PGE2→cAMP→PKA 轴，从而导致芳香酶水平降低。 PPARγ 激动剂可能有助于降低肥胖绝经后女性患激素依赖性乳腺癌的风险。
Estrogen synthesis is catalyzed by cytochrome P450 aromatase, which is encoded by the CYP19 gene. In obese postmenopausal women, increased aromatase activity in white adipose tissue is believed to contribute to hormone-dependent breast cancer. Prostaglandin E2 (PGE2) stimulates the cAMP→protein kinase A (PKA) pathway leading to increased CYP19 transcription and elevated aromatase activity in inflamed white adipose tissue. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE2. Here, we investigated the mechanism by which pioglitazone, a ligand of the nuclear receptor PPARγ suppressed aromatase expression. Treatment of human preadipocytes with pioglitazone suppressed Snail, a repressive transcription factor, resulting in elevated levels of 15-PGDH and reduced levels of PGE2 in the culture medium. Pioglitazone also inhibited cAMP→PKA signaling leading to reduced interaction between phosphorylated cAMP responsive element–binding protein, p300, and CYP19 I.3/II promoter. BRCA1, a repressor of CYP19 transcription, was induced by pioglitazone. Consistent with these in vitro findings, treatment of mice with pioglitazone activated PPARγ, induced 15-PGDH and BRCA1 while suppressing aromatase levels in the mammary gland. Collectively, these results indicate that the activation of PPARγ induces BRCA1 and suppresses the PGE2→cAMP→PKA axis leading to reduced levels of aromatase. PPARγ agonists may have a role in reducing the risk of hormone-dependent breast cancer in obese postmenopausal women.