摘要
卵巢癌(OC)仍然是最具攻击性和致命性的妇科肿瘤,以腹腔大量传播和恶性腹水为特征。癌细胞从原发肿瘤脱落并在腹水微环境进一步转化。这种悬浮过程中,形成多细胞球体,这些聚集物代表一种侵入性和耐药性细胞群它们是转移性传播的根本。EGFR信号通路活化包括增加细胞转移和降低卵巢癌细胞凋亡。EGFR抑制在卵巢癌组织中的应用因其单独治疗时效果不大而受到阻碍。在这项工作中,我们的研究结果主要表明自噬是针对EGFR的特异性抑制剂AGl478在OC细胞系生成球和腹水原球体中诱导产生的,其特点是LC3-II、Beclin1和Atg5的升高。自噬的阻断与3 MA明显提高了悬浮球体的死亡和AG1478诱导细胞的凋亡,表明肿瘤细胞悬液或EGFR抑制在保护细胞自噬作用。因此具有3MA的抑制自噬显著增强了肿瘤细胞在卵巢癌腹腔移植瘤模型腹膜传播中AG1478的抑制作用。此外,升高的EGFR、Beclin1和Atg5的mRNA水平,与卵巢癌患者的生存率的降低相关。综上,我们的研究结果表明,靶向自噬有希望提高EGFR抑制在治疗卵巢癌细胞脱离细胞外基质(ECM)中的效用,这种组合策略可能为控制卵巢癌腹膜转移提供一种新的治疗选择。
关键词: 3-MA,自噬,EGFR抑制,卵巢癌,抗药性,球状体。
图形摘要
Current Cancer Drug Targets
Title:Co-targeting EGFR and Autophagy Impairs Ovarian Cancer Cell Survival during Detachment from the ECM
Volume: 15 Issue: 3
Author(s): Zongyuan Yang, Yi Liu, Xiao Wei, Xiaoshui Zhou, Cheng Gong and Taoran Zhang, Ping Jin, Sen Xu, Ding Ma and Qinglei Gao
Affiliation:
关键词: 3-MA,自噬,EGFR抑制,卵巢癌,抗药性,球状体。
摘要: Ovarian cancer (OC) remains the most aggressive and lethal gynecological tumor characterized by massive intraperitoneal dissemination and malignant ascites. The carcinoma cells exfoliated from the primary tumor and were further transformed in the ascites microenvironment. During this suspension process, multi-cellular spheroids are formed and these aggregates represent an invasive and chemoresistant cellular population fundamental to metastatic dissemination. Activation of EGFR signaling is involved in increased cell metastasis and decreased apoptosis of ovarian cancer. The application of EGFR Inhibition in ovarian cancer was hampered for its limited benefit as a solitary therapy. In this work, our results primarily indicated that autophagy was induced in response to EGFR specific inhibitor AG1478 in OC cell lines generated spheres and ascites primary spheroids, characterized by the elevation of LC3-II, Beclin1 and Atg5. Blockage of autophagy with 3MA notably promoted spheroid death in suspension as well as AG1478-induced cell apoptosis, suggesting a protective autophagy contribution during tumor cells in suspension or under EGFR inhibition. Consequently, inhibiting autophagy with 3MA significantly enhanced the inhibitory effect of AG1478 on tumor cell peritoneal propagation in SKOV3 i.p. xenografts model. In addition, elevated EGFR, Beclin1, and Atg5 mRNA levels were associated with decreased ovarian cancer patient survival. Together, our findings suggested that targeting autophagy held the potential to improve EGFR inhibition benefit in the treatment of ovarian cancer cells during detachment from the extra-cellular matrix (ECM), and that this combination strategy might provide a new treatment option in controlling peritoneal metastasis of ovarian cancer.
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Cite this article as:
Zongyuan Yang, Yi Liu, Xiao Wei, Xiaoshui Zhou, Cheng Gong and Taoran Zhang, Ping Jin, Sen Xu, Ding Ma and Qinglei Gao , Co-targeting EGFR and Autophagy Impairs Ovarian Cancer Cell Survival during Detachment from the ECM, Current Cancer Drug Targets 2015; 15 (3) . https://dx.doi.org/10.2174/1568009615666150126161939
DOI https://dx.doi.org/10.2174/1568009615666150126161939 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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