雷尼霉素M使抗失巢凋亡的H460肺癌细胞对失巢凋亡敏感。

Renieramycin M Sensitizes Anoikis-resistant H460 Lung Cancer Cells to Anoikis.

作者信息

Sirimangkalakitti Natchanun, Chamni Supakarn, Suwanborirux Khanit, Chanvorachote Pithi

机构信息

Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi, Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathumwan, Bangkok, Thailand.

出版信息

Anticancer Res. 2016 Apr;36(4):1665-71.

PMID:27069144

Abstract

BACKGROUND/AIM: Anoikis resistance plays a crucial role in the promotion of survival of circulating tumor cells. This study aimed to evaluate the mechanistic pathways of anoikis resistance in human lung cancer cells and test the possible therapeutic effect of renieramycin M (RM) from the sponge Xestospongia sp. in conversion of anoikis resistance.

MATERIALS AND METHODS

Anoikis-resistant H460 (AR_H460) lung cancer cells in a detached condition were treated with RM at subtoxic concentrations for 24 h. Cell viability, cell morphology, and expression of the proteins involved in survival and apoptotic pathways were determined.

RESULTS

Anoikis resistance in H460 cells is mediated through the up-regulation of survival and anti-apoptotic proteins, namely phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated ATP-dependent tyrosine kinase (p-AKT), B-cell lymphoma-2 (BCL2), and myeloid cell leukemia-1 (MCL1). RM significantly reduced cell viability and inhibited spontaneous aggregation of AR_H460 cells. Western blot analysis revealed that RM suppressed the levels of survival proteins p-ERK and p-AKT and anti-apoptotic proteins BCL2 and MCL1.

CONCLUSION

RM is a potential anti-metastatic agent by sensitizing anoikis-resistant lung cancer cells to anoikis by the suppression of anoikis-resistance mechanisms.

摘要

背景/目的：失巢凋亡抗性在促进循环肿瘤细胞存活中起关键作用。本研究旨在评估人肺癌细胞中失巢凋亡抗性的机制途径，并测试来自海绵Xestospongia sp.的雷尼霉素M（RM）在转化失巢凋亡抗性方面可能的治疗效果。

材料与方法

用亚毒性浓度的RM处理处于 detached 状态的失巢凋亡抗性H460（AR_H460）肺癌细胞24小时。测定细胞活力、细胞形态以及参与存活和凋亡途径的蛋白质表达。

结果

H460细胞中的失巢凋亡抗性是通过上调存活和抗凋亡蛋白介导的，即磷酸化细胞外信号调节激酶（p-ERK）、磷酸化ATP依赖性酪氨酸激酶（p-AKT）、B细胞淋巴瘤-2（BCL2）和髓样细胞白血病-1（MCL1）。RM显著降低细胞活力并抑制AR_H460细胞的自发聚集。蛋白质印迹分析显示，RM抑制了存活蛋白p-ERK和p-AKT以及抗凋亡蛋白BCL2和MCL1的水平。