Cancer and Neurobiology Laboratory, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
Cancer and Neurobiology Laboratory, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
Mitochondrion. 2019 Jan;44:103-110. doi: 10.1016/j.mito.2018.01.006. Epub 2018 Jan 31.
scrib loss of function is associated with various human-cancers. Most of the human-cancers have been characterized by mitochondrial dysfunction with elevated oxidative stress. However, the role of scrib to mitochondrial dysfunction in cancer has not been investigated earlier. Here, we have shown that scrib knockdown leads to mitochondrial depolarization, fragmentation and perinuclear-clustering along with disruption of the redox homeostasis. Moreover, the scrib abrogated tumor showed the elevation of Drp-1 and reduced expression of Marf, which suggests enhanced mitochondrial-fission. Further, the reduced expression of Parkin and HtrA2 interpret defective mitophagy leading to clustering of fragmented mitochondria and apoptotic inhibition in scrib knockdown tumors. Also, Parkin immunostaining depicted its reduced expression and mislocalization in the tumor cells in comparison to wild type. Moreover, the genetic study revealed the epistatic interactions of parkin and scrib. Thus, for the first time our results suggested that scrib loss induced mitochondrial-dysfunction modulates cancer progression by altering the mitochondrial dynamics regulators.
Scrib 缺失功能与多种人类癌症有关。大多数人类癌症的特征是线粒体功能障碍伴氧化应激升高。然而，scrib 对癌症中线粒体功能障碍的作用尚未被早期研究。在这里，我们已经表明 scrib 的敲低导致线粒体去极化、碎片化和核周聚集，同时破坏氧化还原平衡。此外，scrib 缺失的肿瘤显示出 Drp-1 的升高和 Marf 表达的降低，这表明线粒体分裂增强。进一步的，Parkin 和 HtrA2 的表达减少解释了有缺陷的线粒体自噬，导致碎片化线粒体的聚集和 scrib 敲低肿瘤中的凋亡抑制。此外，Parkin 的免疫染色显示其在肿瘤细胞中的表达减少和定位错误，与野生型相比。此外，遗传研究揭示了 parkin 和 scrib 之间的上位性相互作用。因此，我们的研究结果首次表明 scrib 缺失诱导的线粒体功能障碍通过改变线粒体动力学调节剂来调节癌症的进展。
