Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line.
Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line.
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联合使用 MDK 抑制剂可增强 SKOV3 人卵巢癌细胞系中干扰素-γ 的抗肿瘤活性。
DOI：
10.3390/biomedicines11010008
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发表时间：
2022-12-21
期刊：
影响因子：
4.7
通讯作者：
Liu, Jian
中科院分区：
文献类型：
--
作者：
Liu, Qun;Tan, Jingyu;Zhao, Zhenguo;Li, Ruijun;Zheng, Luyu;Chen, Xiangyu;Li, Lina;Dong, Xichen;Wen, Tao;Liu, Jian
由于瘤内异质性、对传统化疗的耐药性以及对靶向治疗和免疫治疗的反应较差，卵巢癌（OC）是一种特别致命的疾病。干扰素-γ（IFN-γ）是一种有吸引力的治疗性细胞因子，在多项OC临床试验中获得了阳性反应。然而，IFN-γ在OC中的临床应用仍然受到阻碍，这是由于当以较高水平使用时的严重毒性，以及当以较低水平使用时的相当大的促转移不良反应。因此，需要有效的联合干预来增强IFN-γ的抗肿瘤功效并抑制IFN-γ诱导的转移。在这里，我们发现OC细胞通过上调中期因子（MDK）来抵消IFN-γ诱导的抗肿瘤活性并促进IFN-γ诱导的转移而形成适应性策略。我们发现MDK是OC中IFN-γ的关键下游靶点，并且这种调节以剂量依赖性方式起作用，并由STAT 1介导。功能获得性研究显示MDK过表达促进OC细胞增殖和转移，提示IFN-γ激活的MDK可能拮抗IFN-γ抑制OC增殖，但协同IFN-γ促进OC转移。随后，我们使用MDK抑制剂（iMDK）评估了MDK抑制对IFN-γ诱导的抗增殖和促转移作用的影响，并且我们发现MDK抑制在体外强烈增强了IFN-γ诱导的生长抑制（所有CI < 0.1）并逆转了IFN-γ驱动的上皮-间充质转化（EMT）和OC中的转移。总的来说，这些数据鉴定了IFN-γ应答蛋白MDK，其在抵消抗增殖的同时赋予IFN-γ在癌症治疗中的促转移作用，因此我们提出在未来的OC治疗中在基于IFN-γ的疗法中组合利用MDK抑制剂。
Ovarian cancer (OC) is a particularly lethal disease due to intratumoral heterogeneity, resistance to traditional chemotherapy, and poor response to targeted therapy and immunotherapy. Interferon-γ (IFN-γ) is an attractive therapeutic cytokine, with positive responses achieved in multiple OC clinical trials. However, clinical application of IFN-γ in OC is still hindered, due to the severe toxicity when used at higher levels, as well as the considerable pro-metastatic adverse effect when used at lower levels. Thus, an effective combined intervention is needed to enhance the anti-tumor efficacy of IFN-γ and to suppress the IFN-γ-induced metastasis. Here, we uncovered that OC cells develop an adaptive strategy by upregulating midkine (MDK) to counteract the IFN-γ-induced anti-tumor activity and to fuel IFN-γ-induced metastasis. We showed that MDK is a critical downstream target of IFN-γ in OC, and that this regulation acts in a dose-dependent manner and is mediated by STAT1. Gain-of-function studies showed that MDK overexpression promotes cell proliferation and metastasis in OC, indicating that IFN-γ-activated MDK may antagonize IFN-γ in inhibiting OC proliferation but synergize IFN-γ in promoting OC metastasis. Subsequently, we assessed the influence of MDK inhibition on IFN-γ-induced anti-proliferation and pro-metastasis effects using an MDK inhibitor (iMDK), and we found that MDK inhibition robustly enhanced IFN-γ-induced growth inhibition (all CIs < 0.1) and reversed IFN-γ-driven epithelial-to-mesenchymal transition (EMT) and metastasis in OC in vitro. Collectively, these data identify an IFN-γ responsive protein, MDK, in counteracting anti-proliferation while endowing the pro-metastatic role of IFN-γ in cancer treatment, and we therefore propose the combined utilization of the MDK inhibitor in IFN-γ-based therapies in future OC treatment.
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影响因子：
6.6
作者：
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