Cell Cycle-Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A.

Autor: Chu TLH; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Connell M; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Zhou L; Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada., He Z; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Won J; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Chen H; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Rahavi SMR; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Mohan P; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Nemirovsky O; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Fotovati A; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Pujana MA; Breast Cancer and Systems Biology Unit, Program Against Cancer Therapeutic Resistance (ProCure), Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain., Reid GSD; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital, Vancouver, British Columbia, Canada., Nielsen TO; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Pante N; Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada., Maxwell CA; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. cmaxwell@bcchr.ca.; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital, Vancouver, British Columbia, Canada.
Jazyk: angličtina
Zdroj: Molecular cancer research : MCR [Mol Cancer Res] 2018 Jan; Vol. 16 (1), pp. 16-31. Date of Electronic Publication: 2017 Oct 09.
DOI: 10.1158/1541-7786.MCR-17-0417
Abstrakt: Cell-cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell-cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multiparameter imaging of wound closure assays was used to track cell-cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell-cycle indicator. Cell migration occurred with an elevated velocity and directionality during the S-G 2 -phase of the cell cycle, and cells in this phase possess front-polarized centrosomes with augmented microtubule nucleation capacity. Inhibition of Aurora kinase-A (AURKA/Aurora-A) dampens these phenotypes without altering cell-cycle progression. During G 2 -phase, the level of phosphorylated Aurora-A at centrosomes is reduced in hyaluronan-mediated motility receptor (HMMR)-silenced cells as is the nuclear transport of TPX2, an Aurora-A-activating protein. TPX2 nuclear transport depends upon HMMR-T703, which releases TPX2 from a complex with importin-α (KPNA2) at the nuclear envelope. Finally, the abundance of phosphorylated HMMR-T703, a substrate for Aurora-A, predicts breast cancer-specific survival and relapse-free survival in patients with estrogen receptor (ER)-negative ( n = 941), triple-negative (TNBC) phenotype ( n = 538), or basal-like subtype ( n = 293) breast cancers, but not in those patients with ER-positive breast cancer ( n = 2,218). Together, these data demonstrate an Aurora-A/TPX2/HMMR molecular axis that intersects cell-cycle progression and cell migration. Implications: Tumor cell engraftment, migration, and cell-cycle progression share common regulation of the microtubule cytoskeleton through the Aurora-A/TPX2/HMMR axis, which has the potential to influence the survival of patients with ER-negative breast tumors. Mol Cancer Res; 16(1); 16-31. ©2017 AACR .
(©2017 American Association for Cancer Research.)
Databáze: MEDLINE
Externí odkaz: