TY - JOUR
T1 - Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation
AU - Wu, Ping Hsiu
AU - Onodera, Yasuhito
AU - Giaccia, Amato J.
AU - Le, Quynh Thu
AU - Shimizu, Shinichi
AU - Shirato, Hiroki
AU - Nam, Jin Min
N1 - Funding Information:
We thank Noriko Sasaki and Keiko Kanno for technical assistant; Mari Horikawa, Midori Tokuda, Machiko Kishi, and Nozomi Sato for administrative work. This work was supported in part by the GI-CoRE/GSQ in Hokkaido University, Grant-in-Aid from Ministry of Education, Science, Sports and Culture of Japan (19K08140 to J.N., 18H02759 to Y.O., 19H03591 to H.S.), and a research grant from The Cell Science Research Foundation to Y.O. Analysis of lysosome distribution was supported by Leica Microsystems.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-020-01339-9
DO - 10.1038/s42003-020-01339-9
M3 - Article
C2 - 33110168
AN - SCOPUS:85094166558
SN - 2399-3642
VL - 3
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 620
ER -
