Co-targeting EGFR and Autophagy Impairs Ovarian Cancer Cell Survival during Detachment from the ECM
Co-targeting EGFR and Autophagy Impairs Ovarian Cancer Cell Survival during Detachment from the ECM
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DOI：
10.2174/1568009615666150126161939
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发表时间：
2015-01-01
影响因子：
3
通讯作者：
Gao, Qinglei
中科院分区：
文献类型：
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作者：
Yang, Zongyuan;Liu, Yi;Gao, Qinglei
卵巢癌（OC）仍然是最具侵袭性和致命性的妇科肿瘤，其特征是大量腹腔内扩散和恶性腹水。癌细胞从原发肿瘤脱落并在腹水微环境中进一步转化。在该悬浮过程中，形成多细胞球状体，并且这些聚集体代表了转移性传播的基础的侵袭性和化学抗性细胞群体。EGFR信号通路的激活参与卵巢癌细胞转移的增加和凋亡的减少。由于单独治疗的益处有限，EGFR抑制在卵巢癌中的应用受到阻碍。在这项工作中，我们的研究结果主要表明，自噬诱导响应EGFR特异性抑制剂AG 1478在OC细胞系产生的球体和腹水原代球体，其特征在于LC 3-II，Beclin 1和Atg 5的升高。用3 MA阻断自噬显著促进悬浮液中的球状体死亡以及AG 1478诱导的细胞凋亡，这表明在悬浮液中或EGFR抑制下的肿瘤细胞期间的保护性自噬贡献。因此，用3 MA抑制自噬显著增强了AG 1478对SKOV 3腹膜内异种移植模型中肿瘤细胞腹膜传播的抑制作用。此外，EGFR、Beclin 1和Atg 5 mRNA水平升高与卵巢癌患者生存率降低相关。总之，我们的研究结果表明，靶向自噬有可能改善EGFR抑制在卵巢癌细胞从细胞外基质（ECM）分离期间的治疗益处，并且这种组合策略可能为控制卵巢癌腹膜转移提供新的治疗选择。
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.