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PSPC1 is a new contextual determinant of aberrant subcellular translocation of oncogenes in tumor progression
Journal of Biomedical Science ( IF 11.0 ) Pub Date : 2021-08-02 , DOI: 10.1186/s12929-021-00753-3
Yaw-Dong Lang , Yuh-Shan Jou

Dysregulation of nucleocytoplasmic shuttling is commonly observed in cancers and emerging as a cancer hallmark for the development of anticancer therapeutic strategies. Despite its severe adverse effects, selinexor, a selective first-in-class inhibitor of the common nuclear export receptor XPO1, was developed to target nucleocytoplasmic protein shuttling and received accelerated FDA approval in 2019 in combination with dexamethasone as a fifth-line therapeutic option for adults with relapsed refractory multiple myeloma (RRMM). To explore innovative targets in nucleocytoplasmic shuttling, we propose that the aberrant contextual determinants of nucleocytoplasmic shuttling, such as PSPC1 (Paraspeckle component 1), TGIF1 (TGF-β Induced Factor Homeobox 1), NPM1 (Nucleophosmin), Mortalin and EBP50, that modulate shuttling (or cargo) proteins with opposite tumorigenic functions in different subcellular locations could be theranostic targets for developing anticancer strategies. For instance, PSPC1 was recently shown to be the contextual determinant of the TGF-β prometastatic switch and PTK6/β-catenin reciprocal oncogenic nucleocytoplasmic shuttling during hepatocellular carcinoma (HCC) progression. The innovative nucleocytoplasmic shuttling inhibitor PSPC1 C-terminal 131 polypeptide (PSPC1-CT131), which was developed to target both the shuttling determinant PSPC1 and the shuttling protein PTK6, maintained their tumor-suppressive characteristics and exhibited synergistic effects on tumor suppression in HCC cells and mouse models. In summary, targeting the contextual determinants of nucleocytoplasmic shuttling with cargo proteins having opposite tumorigenic functions in different subcellular locations could be an innovative strategy for developing new therapeutic biomarkers and agents to improve cancer therapy.

中文翻译:

PSPC1是肿瘤进展中癌基因异常亚细胞易位的新背景决定因素

核细胞质穿梭的失调在癌症中很常见,并成为开发抗癌治疗策略的癌症标志。尽管有严重的副作用,selinexor 是一种选择性一流的常见核输出受体 XPO1 抑制剂,被开发用于靶向核质蛋白穿梭,并于 2019 年与地塞米松联合作为五线治疗选择获得 FDA 的加速批准。成人复发难治性多发性骨髓瘤 (RRMM)。为了探索核质穿梭的创新目标,我们提出了核质穿梭的异常背景决定因素,例如 PSPC1(Paraspeckle 成分 1)、TGIF1(TGF-β 诱导因子同源框 1)、NPM1(核磷蛋白)、Mortalin 和 EBP50,在不同亚细胞位置调节具有相反致瘤功能的穿梭(或货物)蛋白可能是开发抗癌策略的治疗诊断目标。例如,PSPC1 最近被证明是肝细胞癌 (HCC) 进展过程中 TGF-β 前转移开关和 PTK6/β-连环蛋白相互致癌核质穿梭的背景决定因素。创新的核质穿梭抑制剂 PSPC1 C 端 131 多肽 (PSPC1-CT131) 旨在同时靶向穿梭决定簇 PSPC1 和穿梭蛋白 PTK6,保持其肿瘤抑制特性,并在 HCC 细胞和小鼠模型。总之,
更新日期:2021-08-02
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