School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China.
Pharmacol Res. 2021 Dec;174:105939. doi: 10.1016/j.phrs.2021.105939. Epub 2021 Oct 14.
Cancer drug resistance is a formidable obstacle that enhances cancer stem-like cell properties, tumour metastasis and relapse. Luteolin (Lut) is a natural flavonoid with strong antitumor effects. However, the underlying mechanism(s) by which Lut protects against paclitaxel-resistant (PTX-resistant) cancer cell remains unknown. Herein, we found that Lut significantly attenuated the stem-like properties of PTX-resistant cancer cells by downregulating the expression of SOX2 protein. Additionally, further study showed that Lut could inhibit the PI3K/AKT pathway to decrease the phosphorylation level of AKT(S473) and UBR5 expression, which is an ubiquitin E3 ligase that promotes SOX2 degradation. In addition, Lut also inhibited PTX-resistant cancer cell migration and invasion by blocking epithelial-mesenchymal transition (EMT). Importantly, Lut inhibited the tumorigenic ability of oesophageal PTX-resistant cancer cells and showed no obvious toxicity in vivo. Thus, Lut has potential as a promising agent for drug-resistant oesophageal cancer therapy.
癌症耐药性是增强癌症干细胞样细胞特性、肿瘤转移和复发的一个强大障碍。木犀草素（Lut）是一种具有强大抗肿瘤作用的天然类黄酮。然而，Lut 防止紫杉醇耐药（PTX 耐药）癌细胞的潜在机制尚不清楚。在此，我们发现 Lut 通过下调 SOX2 蛋白的表达显著减弱了 PTX 耐药癌细胞的干细胞样特性。此外，进一步的研究表明，Lut 可以抑制 PI3K/AKT 通路，降低 AKT(S473)和 UBR5 表达的磷酸化水平，UBR5 是一种促进 SOX2 降解的泛素 E3 连接酶。此外，Lut 通过阻断上皮-间充质转化（EMT）也抑制了 PTX 耐药癌细胞的迁移和侵袭。重要的是，Lut 抑制了食管 PTX 耐药癌细胞的致瘤能力，并且在体内没有明显的毒性。因此，Lut 有可能成为治疗耐药性食管癌的一种有前途的药物。
