Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation
Year: 2020
Type: article
Abstract: 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.
Source: Communications Biology
Institutions: Hokkaido University, Stanford Medicine, Stanford University
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,290
Awards: G108552419, Analysis of the mechanisms by which intra-tumor metabolic microenvironment leads to radioresistance, Analysis of cell-to-cell communication to identify novel targets of radiotherapy, Research and development about helium and proton hybrid system with proton CT and Immuno-radiotherapy, G5522554483, G767425150
OpenAlex ID: W3096146045