Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation

Tomas Garzon-Muvdi, Paula Schiapparelli, Colette ap Rhys, Hugo Guerrero Cazares, Christopher Smith, Deok Ho Kim, Lyonell Kone, Harrison Farber, Danielle Y. Lee, Steven S. An, Andre Levchenko, Alfredo Quinones-Hinojosa

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na+-K+-Cl- cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.

Original languageEnglish (US)
Article numbere1001320
JournalPLoS Biology
Volume10
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

Fingerprint

Sodium-Potassium-Chloride Symporters
Focal Adhesions
Brain Neoplasms
adhesion
Tumors
Brain
Adhesion
Glioma
brain
neoplasms
Glioblastoma
Cell Movement
cells
cell movement
traction (mechanics)
aggression
phosphotransferases (kinases)
Phosphotransferases
Ions
Tissue

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. / Garzon-Muvdi, Tomas; Schiapparelli, Paula; ap Rhys, Colette; Guerrero Cazares, Hugo; Smith, Christopher; Kim, Deok Ho; Kone, Lyonell; Farber, Harrison; Lee, Danielle Y.; An, Steven S.; Levchenko, Andre; Quinones-Hinojosa, Alfredo.

In: PLoS Biology, Vol. 10, No. 5, e1001320, 05.2012.

Research output: Contribution to journalArticle

Garzon-Muvdi, T, Schiapparelli, P, ap Rhys, C, Guerrero Cazares, H, Smith, C, Kim, DH, Kone, L, Farber, H, Lee, DY, An, SS, Levchenko, A & Quinones-Hinojosa, A 2012, 'Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation', PLoS Biology, vol. 10, no. 5, e1001320. https://doi.org/10.1371/journal.pbio.1001320
Garzon-Muvdi, Tomas ; Schiapparelli, Paula ; ap Rhys, Colette ; Guerrero Cazares, Hugo ; Smith, Christopher ; Kim, Deok Ho ; Kone, Lyonell ; Farber, Harrison ; Lee, Danielle Y. ; An, Steven S. ; Levchenko, Andre ; Quinones-Hinojosa, Alfredo. / Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. In: PLoS Biology. 2012 ; Vol. 10, No. 5.
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