Alantolactone inhibits cervical cancer progression by downregulating BMI1.
Alantolactone inhibits cervical cancer progression by downregulating BMI1.
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Alantolactone 通过下调 BMI1 抑制宫颈癌进展
DOI：
10.1038/s41598-021-87781-z
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发表时间：
2021-04-29
影响因子：
4.6
通讯作者：
Sang M
中科院分区：
文献类型：
--
作者：
Sun X;Xu H;Dai T;Xie L;Zhao Q;Hao X;Sun Y;Wang X;Jiang N;Sang M
子宫颈癌是女性中第二常见的癌症。尽管宫颈癌治疗取得了进展，但肿瘤复发和转移仍然是导致死亡的主要原因。BMI1高表达与宫颈癌肿瘤分化差、临床分级高、预后差有显著相关性，是宫颈癌独立的预后因素。Alantolactone （AL）是一种倍半萜内酯，具有有效的抗炎和抗癌活性。本文探讨AL在降低HeLa和SiHa宫颈癌细胞增殖、迁移、侵袭以及促进线粒体损伤和自噬中的作用机制。BMI1沉默降低HeLa细胞上皮-间充质转化相关蛋白，增加自噬相关蛋白。这些作用被HeLa细胞中BMI1的过表达逆转。因此，在HeLa细胞中，BMI1的表达与侵袭呈正相关，与自噬负相关。重要的是，AL降低了HeLa异种移植肿瘤的重量、体积和BMI1的表达。此外，利用分子对接软件Autodock Vina对BMI1的结构和AL的靶标相互作用进行了虚拟筛选；AL降低了N-cadherin、vimentin、P62的表达，增加了LC3B、Beclin-1在异种移植肿瘤中的表达。最后，BMI1的表达增加了STAT3的磷酸化，STAT3对细胞增殖、存活、迁移和侵袭至关重要。因此，我们认为AL在抑制BMI1在宫颈癌发生中起关键作用，是一种潜在的宫颈癌治疗剂。
Cervical cancer is the second most common cancer in women. Despite advances in cervical cancer therapy, tumor recurrence and metastasis remain the leading causes of mortality. High expression of BMI1 is significantly associated with poor tumor differentiation, high clinical grade, and poor prognosis of cervical cancer, and is an independent prognostic factor in cervical carcinoma. Alantolactone (AL), a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities. In this paper, we investigated the mechanism of AL in reducing the proliferation, migration, and invasion of HeLa and SiHa cervical cancer cells as well as its promotion of mitochondrial damage and autophagy. BMI1 silencing decreased epithelial-mesenchymal transformation-associated proteins and increased autophagy-associated proteins in HeLa cells. These effects were reversed by overexpression of BMI1 in HeLa cells. Thus, BMI1 expression is positively correlated with invasion and negatively correlated with autophagy in HeLa cells. Importantly, AL decreased the weight, volume, and BMI1 expression in HeLa xenograft tumors. Furthermore, the structure of BMI1 and target interaction of AL were virtually screened using the molecular docking program Autodock Vina; AL decreased the expression of N-cadherin, vimentin, and P62 and increased the expression of LC3B and Beclin-1 in xenograft tumors. Finally, expression of BMI1 increased the phosphorylation of STAT3, which is important for cell proliferation, survival, migration, and invasion. Therefore, we suggest that AL plays a pivotal role in inhibiting BMI1 in the tumorigenesis of cervical cancer and is a potential therapeutic agent for cervical cancer.