Yang Zongyuan, Liu Yi, Wei Xiao, Zhou Xiaoshui, Gong Cheng, Zhang Taoran, Jin Ping, Xu Sen, Ma Ding, Gao Qinglei
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv. Wuhan, Hubei 430030, China.
Curr Cancer Drug Targets. 2015;15(3):215-26. doi: 10.2174/1568009615666150126161939.
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.
卵巢癌（OC）仍然是最具侵袭性和致死性的妇科肿瘤，其特征是大量腹膜内播散和恶性腹水。从原发性肿瘤脱落的癌细胞在腹水微环境中进一步转化。在这个悬浮过程中，形成了多细胞球体，这些聚集体代表了转移播散所必需的侵袭性和化疗耐药性细胞群体。表皮生长因子受体（EGFR）信号的激活与卵巢癌细胞转移增加和凋亡减少有关。EGFR抑制在卵巢癌中的应用因其作为单一疗法的益处有限而受到阻碍。在这项研究中，我们的结果主要表明，在产生球体的OC细胞系和腹水原发性球体中，自噬是由EGFR特异性抑制剂AG1478诱导的，其特征是微管相关蛋白1轻链3-II（LC3-II）、Beclin1和自噬相关蛋白5（Atg5）升高。用3-甲基腺嘌呤（3MA）阻断自噬显著促进了悬浮球体的死亡以及AG1478诱导的细胞凋亡，表明在悬浮或EGFR抑制下的肿瘤细胞中自噬具有保护作用。因此，在SKOV3腹腔异种移植模型中，用3MA抑制自噬显著增强了AG1478对肿瘤细胞腹膜增殖的抑制作用。此外，EGFR、Beclin1和Atg5 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，靶向自噬有可能在卵巢癌细胞从细胞外基质（ECM）脱离过程中提高EGFR抑制的疗效，并且这种联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。
