Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRβ-IL-6 axis in MUC1-positive cervical cancer
Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRβ-IL-6 axis in MUC1-positive cervical cancer
复制标题
厄洛替尼通过阻断 MUC1 阳性宫颈癌中的 EGFR-CREB/GRβ-IL-6 轴来克服紫杉醇耐药的癌症干细胞
DOI：
10.1038/s41389-019-0179-2
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发表时间：
2019-11-26
期刊：
影响因子：
6.2
通讯作者：
Huang, Lei
中科院分区：
文献类型：
--
作者：
Lv, Yaping;Cang, Wei;Huang, Lei
Cancer stem cells (CSCs) are often enriched after chemotherapy and contribute to tumor relapse. While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of diverse types of cancer, whether EGFR-TKIs are effective against chemoresistant CSCs in cervical cancer is largely unknown. Here, we reveal that EGFR correlates with reduced disease-free survival in cervical cancer patients with chemotherapy. Erlotinib, an EGFR-TKI, effectively impedes CSCs enrichment in paclitaxel-resistant cells through inhibiting IL-6. In this context, MUC1 induces CSCs enrichment in paclitaxel-resistant cells via activation of EGFR, which directly enhances IL-6 transcription through cAMP response element-binding protein (CREB) and glucocorticoid receptor β (GRβ). Treatment with erlotinib sensitizes CSCs to paclitaxel therapy both in vitro and in vivo. More importantly, positive correlations between the expressions of MUC1, EGFR, and IL-6 were found in 20 cervical cancer patients after chemotherapy. Mining TCGA data sets also uncovered the expressions of MUC1-EGFR-IL-6 correlates with poor disease-free survival in chemo-treated cervical cancer patients. Collectively, our work has demonstrated that the MUC1-EGFR-CREB/GRβ axis stimulates IL-6 expression to induce CSCs enrichment and importantly, this effect can be abrogated by erlotinib, uncovering a novel strategy to treat paclitaxel-resistant cervical cancer.
