Ursolic acid (UA) has been shown to suppress various tumor progression, however, its roles in Adriamycin resistance of human ovarian cancer (OC) cells are still unclear. This work aims to investigate the effects of UA on the Adriamycin resistance of human OC cells. Here, we constructed Adriamycin‐resistant OC SKOV3‐Adr cells and found that UA attenuated Adriamycin resistance in SKOV3‐Adr cells. Additionally, UA enhanced Adriamycin sensitivity in the parental SKOV3 and another OC cell line A2780 cells. Mechanistic studies showed that HuR mRNA level was similar between SKOV3 and SKOV3‐Adr cells, but the cytoplasmic expression of HuR protein was increased in SKOV3‐Adr cells compared with that in SKOV3 cells, and subsequently enhancing the mRNA stability of multidrug resistance gene 1 (MDR1). Moreover, UA had no effects on HuR expression, but promoted the cytoplasm‐nucleus translocation of HuR protein, decreased MDR1 mRNA stability and thus reduced MDR1 expression. Furthermore, overexpression of MDR1 rescued the effects of UA on Adriamycin resistance and sensitivity. This work reveals a novel HuR/MDR1 axis responsible for UA‐mediated attenuation on Adriamycin resistance in OC cells.

中文翻译：

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熊果酸通过促进HuR从细胞质到细胞核的易位降低人卵巢癌细胞的阿霉素耐药性


熊果酸（UA）已被证明可以抑制多种肿瘤进展，然而，其在人卵巢癌（OC）细胞阿霉素耐药中的作用仍不清楚。本工作旨在探讨UA对人OC细胞阿霉素耐药性的影响。在这里，我们构建了阿霉素耐药性 OC SKOV3-Adr 细胞，发现 UA 减弱了 SKOV3-Adr 细胞中的阿霉素耐药性。此外，UA 增强亲本 SKOV3 和另一种 OC 细胞系 A2780 细胞中的阿霉素敏感性。机制研究表明，SKOV3和SKOV3-Adr细胞之间的HuR mRNA水平相似，但与SKOV3细胞相比，SKOV3-Adr细胞中HuR蛋白的胞质表达增加，从而增强了多药耐药基因1的mRNA稳定性（耐多药1）。此外，UA对HuR的表达没有影响，但促进HuR蛋白的胞质核易位，降低MDR1 mRNA的稳定性，从而降低MDR1的表达。此外，MDR1 的过度表达挽救了 UA 对阿霉素耐药性和敏感性的影响。这项工作揭示了一种新的 HuR/MDR1 轴，负责 UA 介导的 OC 细胞中阿霉素耐药性的减弱。