Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins
Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins
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DOI：
10.1038/s41419-019-2117-9
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发表时间：
2019-11-20
影响因子：
9
通讯作者：
Sasaki, Hiroki
中科院分区：
文献类型：
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作者：
Takeda, Takashi;Komatsu, Masayuki;Sasaki, Hiroki
宫颈癌是世界上最常见的妇科恶性肿瘤；然而，晚期和复发性宫颈癌患者的生存率仍然很低。多面蛋白胰岛素样生长因子 2 受体 (IGF2R) 具有多种配体，表示为 IGF-2 和甘露糖 6-磷酸 (M6P) 标记蛋白。关于其作为IGF1R信号的拮抗活性，IGF2R目前被认为是肿瘤抑制基因，而其作为M6P受体的意义仍不清楚。在此，基于 TCGA 和 GEO 开放数据集的转录组分析，我们发现 IGF2R 上调并与宫颈癌不良预后相关。使用宫颈癌细胞系的多项实验表明，IGF2R 耗竭会诱导细胞凋亡，降低细胞活力，并增加对某些抗癌药物顺铂的敏感性。与IGF1R信号传导的微不足道的影响相反，IGF2R的缺失破坏了M6P标记的组织蛋白酶从高尔基体到溶酶体的转运，导致溶酶体活性降低，其异常积累和自噬和线粒体自噬功能障碍，导致错误折叠蛋白的积累和活性氧的产生。总而言之，IGF2R 通过在宫颈癌中运输 M6P 标记的货物而具有致癌作用，可用作预后分类的预测生物标志物。
Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal, IGF2R is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.