Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression-An in vitro study
Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression-An in vitro study
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DOI：
10.1371/journal.pone.0228024
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发表时间：
2020-01-24
期刊：
影响因子：
3.7
通讯作者：
Brard, Laurent
中科院分区：
文献类型：
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作者：
Ayyagari, Vijayalakshmi N.;Wang, Xinjia;Brard, Laurent
酰基辅酶A胆固醇酰基转移酶-1（ACAT-1）介导的胆固醇酯的异常积累已被证明有助于各种癌症（包括白血病、神经胶质瘤、乳腺癌、胰腺癌和前列腺癌）的癌症进展。然而，ACAT-1和胆固醇酯（CE）在卵巢癌中的意义相对研究不足。在这项体外研究中，我们评估了ACAT-1在卵巢癌进展中的表达和作用。我们观察到一组卵巢癌细胞系（OC-314，SKOV-3和IGF-I）中ACAT-1和CE水平的表达与原代卵巢上皮细胞（正常对照）相比显著增加。为了证实ACAT 1的肿瘤促进能力，我们通过用ACAT抑制剂avasimibe处理我们的细胞系或通过用ACAT-1特异性短发夹RNA（shRNA）稳定转染来抑制ACAT-1表达和活性。我们观察到，与各自的对照（用乱序shRNA转染的细胞系）相比，ACAT-1敲除卵巢癌细胞系的细胞增殖、迁移和侵袭受到显着抑制。ACAT-1抑制增强凋亡，同时增加半胱天冬酶3/7活性和降低线粒体膜电位。活性氧（ROS）生成增加与p53表达增加可能是ACAT-1抑制的促凋亡作用的潜在机制。此外，ACAT-1抑制卵巢癌细胞系显示出对顺铂治疗的化疗敏感性增强。这些结果表明ACAT-1可能是卵巢癌治疗的潜在新靶点。
Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT-1) mediated cholesterol ester has been shown to contribute to cancer progression in various cancers including leukemia, glioma, breast, pancreatic and prostate cancers. However, the significance of ACAT-1 and cholesterol esters (CE) is relatively understudied in ovarian cancer. In this in vitro study, we assessed the expression and contribution of ACAT-1 in ovarian cancer progression. We observed a significant increase in the expression of ACAT-1 and CE levels in a panel of ovarian cancer cell lines (OC-314, SKOV-3 and IGROV-1) compared to primary ovarian epithelial cells (normal controls). To confirm the tumor promoting capacity of ACAT1, we inhibited ACAT-1 expression and activity by treating our cell lines with an ACAT inhibitor, avasimibe, or by stable transfection with ACAT-1 specific short hairpin RNA (shRNA). We observed significant suppression of cell proliferation, migration and invasion in ACAT-1 knockdown ovarian cancer cell lines compared to their respective controls (cell lines transfected with scrambled shRNA). ACAT-1 inhibition enhanced apoptosis with a concurrent increase in caspases 3/7 activity and decreased mitochondrial membrane potential. Increased generation of reactive oxygen species (ROS) coupled with increased expression of p53 may be the mechanism(s) underlying pro-apoptotic action of ACAT-1 inhibition. Additionally, ACAT-1 inhibited ovarian cancer cell lines displayed enhanced chemosensitivity to cisplatin treatment. These results suggest ACAT-1 may be a potential new target for the treatment of ovarian cancer.