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Mitochondria chaperone GRP75 moonlighting as a cell cycle controller to derail endocytosis provides an opportunity for nanomicrosphere intracellular delivery

Gao, Zhihui; Niu, Xiuran; Zhang, Qing; Chen, Hang; Gao, Aiai; Qi, Shanshan; Xiang, Rong; Belting, Mattias LU and Zhang, Sihe LU (2017) In Oncotarget 8(35). p.58536-58552
Abstract

Understanding how cancer cells regulate endocytosis during the cell cycle could lead us to capitalize this event pharmacologically. Although certain endocytosis pathways are attenuated during mitosis, the endocytosis shift and regulation during the cell cycle have not been well clarified. The conventional concept of glucose-regulated proteins (GRPs) as protein folding chaperones was updated by discoveries that translocated GRPs assume moonlighting functions that modify the immune response, regulate viral release, and control intracellular trafficking. In this study, GRP75, a mitochondria matrix chaperone, was discovered to be highly expressed in mitotic cancer cells. Using synchronized cell models and the GRP75 gene knockdown and... (More)

Understanding how cancer cells regulate endocytosis during the cell cycle could lead us to capitalize this event pharmacologically. Although certain endocytosis pathways are attenuated during mitosis, the endocytosis shift and regulation during the cell cycle have not been well clarified. The conventional concept of glucose-regulated proteins (GRPs) as protein folding chaperones was updated by discoveries that translocated GRPs assume moonlighting functions that modify the immune response, regulate viral release, and control intracellular trafficking. In this study, GRP75, a mitochondria matrix chaperone, was discovered to be highly expressed in mitotic cancer cells. Using synchronized cell models and the GRP75 gene knockdown and ectopic overexpression strategy, we showed that: (1) clathrin-mediated endocytosis (CME) was inhibited whereas clathrinindependent endocytosis (CIE) was unchanged or even up-regulated in the cell cycle M-phase; (2) GRP75 inhibited CME but promoted CIE in the M-phase, which is largely due to its high expression in cancer cell mitochondria; (3) GRP75 targeting by its small molecular inhibitor MKT-077 enhanced cell cycle G1 phase-privileged CME, which provides an opportunity for intracellular delivery of nanomicrospheres sized from 40 nm to 100 nm. Together, our results revealed that GRP75 moonlights as a cell cycle controller and endocytosis regulator in cancer cells, and thus has potential as a novel interference target for nanoparticle drugs delivery into dormant cancer cells.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell cycle, Clathrin-independent endocytosis, Clathrin-mediated endocytosis, GRP75, Nanomicrosphere
in
Oncotarget
volume
8
issue
35
pages
17 pages
publisher
Impact Journals, LLC
external identifiers
  • scopus:85029041414
  • wos:000408941900052
ISSN
1949-2553
DOI
10.18632/oncotarget.17234
language
English
LU publication?
yes
id
23efed06-f0cf-485a-afe8-e846815c70e5
date added to LUP
2017-10-10 08:41:06
date last changed
2018-01-16 13:22:17
@article{23efed06-f0cf-485a-afe8-e846815c70e5,
  abstract     = {<p>Understanding how cancer cells regulate endocytosis during the cell cycle could lead us to capitalize this event pharmacologically. Although certain endocytosis pathways are attenuated during mitosis, the endocytosis shift and regulation during the cell cycle have not been well clarified. The conventional concept of glucose-regulated proteins (GRPs) as protein folding chaperones was updated by discoveries that translocated GRPs assume moonlighting functions that modify the immune response, regulate viral release, and control intracellular trafficking. In this study, GRP75, a mitochondria matrix chaperone, was discovered to be highly expressed in mitotic cancer cells. Using synchronized cell models and the GRP75 gene knockdown and ectopic overexpression strategy, we showed that: (1) clathrin-mediated endocytosis (CME) was inhibited whereas clathrinindependent endocytosis (CIE) was unchanged or even up-regulated in the cell cycle M-phase; (2) GRP75 inhibited CME but promoted CIE in the M-phase, which is largely due to its high expression in cancer cell mitochondria; (3) GRP75 targeting by its small molecular inhibitor MKT-077 enhanced cell cycle G1 phase-privileged CME, which provides an opportunity for intracellular delivery of nanomicrospheres sized from 40 nm to 100 nm. Together, our results revealed that GRP75 moonlights as a cell cycle controller and endocytosis regulator in cancer cells, and thus has potential as a novel interference target for nanoparticle drugs delivery into dormant cancer cells.</p>},
  author       = {Gao, Zhihui and Niu, Xiuran and Zhang, Qing and Chen, Hang and Gao, Aiai and Qi, Shanshan and Xiang, Rong and Belting, Mattias and Zhang, Sihe},
  issn         = {1949-2553},
  keyword      = {Cell cycle,Clathrin-independent endocytosis,Clathrin-mediated endocytosis,GRP75,Nanomicrosphere},
  language     = {eng},
  number       = {35},
  pages        = {58536--58552},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Mitochondria chaperone GRP75 moonlighting as a cell cycle controller to derail endocytosis provides an opportunity for nanomicrosphere intracellular delivery},
  url          = {http://dx.doi.org/10.18632/oncotarget.17234},
  volume       = {8},
  year         = {2017},
}