Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors
Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors
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DOI：
10.1158/0008-5472.can-06-3735
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Chintharlapalli, Sudhakar;Papineni, Sabitha;Safe, Stephen
白桦酸是一种五环三萜天然产物，最初被确定为黑色素瘤特异性细胞毒素，在动物模型中表现出低毒性。随后的研究表明，白桦酸可诱导多组织肿瘤细胞凋亡和抗血管生成反应；然而，其作用机制尚不清楚。以LNCaP前列腺癌细胞为模型，我们现在发现白桦酸降低血管内皮生长（VEGF）和抗凋亡蛋白survivin的表达。在LNCaP细胞和肿瘤中，这些白桦酸诱导的抗血管生成和促凋亡反应的机制是由于活化了选择性蛋白酶体依赖的转录因子特异性蛋白1 （Sp1）、Sp3和Sp4的降解，这些特异性蛋白调节VEGF和survivin的表达。因此，白桦酸通过靶向降解肿瘤中高度过表达的Sp蛋白作为一种新型抗癌剂。
Betulinic acid is a pentacyclic triterpene natural product initially identified as a melanoma-specific cytotoxic agent that exhibits low toxicity in animal models. Subsequent studies show that betulinic acid induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues; however, the underlying mechanism of action is unknown. Using LNCaP prostate cancer cells as a model, we now show that betulinic acid decreases expression of vascular endothelial growth (VEGF) and the antiapoptotic protein survivin. The mechanism of these betulinic acid-induced antiangiogenic and proapoptotic responses in both LNCaP cells and in tumors is due to activation of selective proteasome-dependent degradation of the transcription factors specificity protein 1 (Sp1), Sp3, and Sp4, which regulate VEGF and survivin expression. Thus, betulinic acid acts as a novel anticancer agent through targeted degradation of Sp proteins that are highly overexpressed in tumors.