Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14-mediated mechanism.
Although mitochondrial dysfunction and reactive oxygen species (ROS) stress have long been observed in cancer cells, their role in promoting malignant cell behavior remains unclear. Here, we show that perturbation of the mitochondrial respiratory chain in breast cancer cells leads to a generation of subclones of cells with increased ROS, active proliferation, high cellular motility, and invasive behaviors in vitro and in vivo. Gene expression analysis using microarrays revealed that all subclones overexpressed CXCL14, a novel chemokine with undefined function. We further show that CXCL14 expression is up-regulated by ROS through the activator protein-1 signaling pathway and promotes cell motility through elevation of cytosolic Ca(2+) by binding to the inositol 1,4,5-trisphosphate receptor on the endoplasmic reticulum. Abrogation of CXCL14 expression using a decoy approach suppressed cell motility and invasion. Our data suggest that mitochondrial dysfunction and ROS stress promote cancer cell motility through a novel pathway mediated by CXCL14.
Pelicano
Helene
H
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Lu
Weiqin
W
Zhou
Yan
Y
Zhang
Wan
W
Chen
Zhao
Z
Hu
Yumin
Y
Huang
Peng
P
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D019743:Chemokines, CXC / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D002118:Calcium