Targeted apoptosis in ovarian cancer cells through mitochondrial dysfunction in response to Sambucus nigra agglutinin.
Targeted apoptosis in ovarian cancer cells through mitochondrial dysfunction in response to Sambucus nigra agglutinin.
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DOI：
10.1038/cddis.2017.77
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发表时间：
2017-05-04
影响因子：
9
通讯作者：
Roy SS
中科院分区：
文献类型：
--
作者：
Chowdhury SR;Ray U;Chatterjee BP;Roy SS
卵巢癌（OC）患者面临着严峻的挑战，临床治疗，由于缺乏筛查措施，化疗耐药性和最终缺乏无毒的治疗。癌细胞采用各种防御策略来维持肿瘤微环境，其中失调的凋亡仍然是癌症进展的多功能促进剂。虽然最近的研究集中在识别能够诱导癌细胞凋亡的药物，但有效破坏其生存优势的分子尚未分类。在这里，我们鉴定了凝集素，黑接骨木凝集素（SNA），凭借其对α-2，6-连接的唾液酸的特异性识别，对鉴定OC表现出选择性。SNA与OC细胞的表面结合证实了疾病的高唾液酸化状态。此外，SNA激活AKT和ERK 1/2的信号通路，最终促进动力蛋白相关蛋白-1（Drp-1）的去磷酸化。在其易位到线粒体分裂位点后，Drp-1介导线粒体表型中的开关的中心作用，以获得片段化形态。我们证实了线粒体外膜透化导致ROS的产生和细胞色素C释放到胞质溶胶中。SNA反应导致生物能量学特征从瓦尔堡表型向线粒体氧化磷酸化升高的相关转变，这完全突出了线粒体功能障碍在抑制癌症进展中的参与。不能补充SNA诱导的能量紧缩的增殖癌细胞的干扰呼吸结果的事件导致细胞周期停滞在G2/M期之前。我们的研究结果定位SNA在一个关键时刻，它被证明是一个有前途的候选人阻碍进展的OC。总之，我们揭示了识别天然分子的新方面，这些分子具有靶向线粒体结构动力学的固有能力，为开发用于治疗OC的无毒疗法奠定了基础。
Ovarian carcinoma (OC) patients encounter the severe challenge of clinical management owing to lack of screening measures, chemoresistance and finally dearth of non-toxic therapeutics. Cancer cells deploy various defense strategies to sustain the tumor microenvironment, among which deregulated apoptosis remains a versatile promoter of cancer progression. Although recent research has focused on identifying agents capable of inducing apoptosis in cancer cells, yet molecules efficiently breaching their survival advantage are yet to be classified. Here we identify lectin, Sambucus nigra agglutinin (SNA) to exhibit selectivity towards identifying OC by virtue of its specific recognition of α-2, 6-linked sialic acids. Superficial binding of SNA to the OC cells confirm the hyper-sialylated status of the disease. Further, SNA activates the signaling pathways of AKT and ERK1/2, which eventually promotes de-phosphorylation of dynamin-related protein-1 (Drp-1). Upon its translocation to the mitochondrial fission loci Drp-1 mediates the central role of switch in the mitochondrial phenotype to attain fragmented morphology. We confirmed mitochondrial outer membrane permeabilization resulting in ROS generation and cytochrome-c release into the cytosol. SNA response resulted in an allied shift of the bioenergetics profile from Warburg phenotype to elevated mitochondrial oxidative phosphorylation, altogether highlighting the involvement of mitochondrial dysfunction in restraining cancer progression. Inability to replenish the SNA-induced energy crunch of the proliferating cancer cells on the event of perturbed respiratory outcome resulted in cell cycle arrest before G2/M phase. Our findings position SNA at a crucial juncture where it proves to be a promising candidate for impeding progression of OC. Altogether we unveil the novel aspect of identifying natural molecules harboring the inherent capability of targeting mitochondrial structural dynamics, to hold the future for developing non-toxic therapeutics for treating OC.
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影响因子：
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通讯作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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