Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation.
Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation.
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DOI：
10.1038/s42003-020-01339-9
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发表时间：
2020-10-27
影响因子：
5.9
通讯作者：
Nam JM
中科院分区：
文献类型：
--
作者：
Wu PH;Onodera Y;Giaccia AJ;Le QT;Shimizu S;Shirato H;Nam JM
增强的侵袭性，转移和预后不良的一个关键决定因素，已被观察到在癌症治疗，包括放射治疗存活的癌细胞。在这里，我们表明，在辐射存活的癌细胞的侵袭性与溶酶体胞吐作用的变化引起的增强激活的Arl 8b，一个小的GTdR，调节溶酶体运输。辐射后，通过调节BORC亚基，Ar 18 b与其效应物SKIP的结合增加。Arl 8b或BORC亚基的敲低降低了溶酶体胞吐作用和辐射存活细胞的侵袭性。值得注意的是，ARL 8B和BORC亚基基因的高表达与乳腺癌患者的不良预后显著相关。Sp1是一种ATM调控的转录因子，它能增加辐射后BORC亚基基因的表达。体内实验表明，Arl 8b的消融降低了IR诱导的侵袭性肿瘤生长和远处转移。这些发现表明BORC-Arl 8b介导的溶酶体运输是通过抑制侵袭性肿瘤生长和转移来改善放射治疗的靶标。Wu等人发现了Arl 8b依赖性溶酶体运输和胞吐作用在促进乳腺癌细胞和在辐射治疗中存活的肿瘤的侵袭和转移中的作用。这些发现提供的见解，可能有助于未来的战略，以改善放射治疗的结果。
Enhanced invasiveness, a critical determinant of metastasis and poor prognosis, has been observed in cancer cells that survive cancer therapy, including radiotherapy. Here, we show that invasiveness in radiation-surviving cancer cells is associated with alterations in lysosomal exocytosis caused by the enhanced activation of Arl8b, a small GTPase that regulates lysosomal trafficking. The binding of Arl8b with its effector, SKIP, is increased after radiation through regulation of BORC-subunits. Knockdown of Arl8b or BORC-subunits decreases lysosomal exocytosis and the invasiveness of radiation-surviving cells. Notably, high expression of ARL8B and BORC-subunit genes is significantly correlated with poor prognosis in breast cancer patients. Sp1, an ATM-regulated transcription factor, is found to increase BORC-subunit genes expression after radiation. In vivo experiments show that ablation of Arl8b decreases IR-induced invasive tumor growth and distant metastasis. These findings suggest that BORC-Arl8b-mediated lysosomal trafficking is a target for improving radiotherapy by inhibiting invasive tumor growth and metastasis. Wu et al. discover a role for Arl8b-dependent lysosomal trafficking and exocytosis in promoting invasion and metastasis of breast cancer cells and tumours that survive irradiation treatment. These findings provide insights that may aid future strategies to improve radiotherapy outcome.
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影响因子：
50.3
作者：
Anh Tuan Nguyen;Chia, Joanne;Bard, Frederic
通讯作者：
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作者：
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作者：
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DOI：
10.1073/pnas.1500722112
发表时间：
2015-07-14
影响因子：
11.1
作者：
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通讯作者：
Altieri, Dario C.
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影响因子：
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作者：
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