During the previous funding period we showed that glioma cells shrink as they invade the narrow extracellular spaces in the brain. Cell shrinkage is energetically driven by K+ and Cl- efflux through ion channels, which osmotically drives water out of the cell. We identified the underlying Cl-, and Ca2+-activated K+ channels and demonstrated that their pharmacological inhibition renders glioma cells unable to invade. One of the underlying channels, ClC-3, is regulated by chlorotoxin, a scorpion-derived peptide that inhibits Cl- currents and retards glioma invasion. These finding led us to initiate a Phase I/II clinical trial examining chlorotoxin as an anti-tumor drug in patients with malignant glioma which is now in Phase II. This competitive renewal application expands on unexpected observations made that mechanistically link Cl- movement to cell volume changes that occur in the context of cell proliferation and terminal cell proliferation, i.e. apoptosis. Specifically we hypothesize that glioma cells maintain elevated intracellular Cl- through active ion transport, which in turn allows cells to release Cl- through channels as they condense to enter mitosis. Cell shrinkage is directly caused by Cl- efflux and its inhibition inhibits proliferation. It also prevents condensation preceding apoptosis. Following each cell division cells re- establish their original volume through transport mediated Cl-/K+ and water uptake, which again is a necessary step for cell growth.
4 Specific aims are proposed that study the underlying Cl- channels and transporters, their mechanistic role in cell volume changes associated with proliferation and apoptosis as well as their regulation by phosphorylation and membrane trafficking. Finally, two FDA approved Cl- transport inhibitors will be examined preclinically using an animal model for malignant glioma.
This competitive renewal application expands on unexpected observations made that mechanistically link Cl- movement to cell volume changes that occur in the context of cell proliferation and terminal cell proliferation, i.e. apoptosis.
|Campbell, Susan L; Robel, Stefanie; Cuddapah, Vishnu A et al. (2015) GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy. Glia 63:23-36|
|Turner, Kathryn L; Sontheimer, Harald (2014) Cl- and K+ channels and their role in primary brain tumour biology. Philos Trans R Soc Lond B Biol Sci 369:20130095|
|Robert, Stephanie M; Sontheimer, Harald (2014) Glutamate transporters in the biology of malignant gliomas. Cell Mol Life Sci 71:1839-54|
|Turner, Kathryn L; Sontheimer, Harald (2014) KCa3.1 modulates neuroblast migration along the rostral migratory stream (RMS) in vivo. Cereb Cortex 24:2388-400|
|Cuddapah, Vishnu Anand; Robel, Stefanie; Watkins, Stacey et al. (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15:455-65|
|Honasoge, Avinash; Shelton, Katherine A; Sontheimer, Harald (2014) Autocrine regulation of glioma cell proliferation via pHe-sensitive K(+) channels. Am J Physiol Cell Physiol 306:C493-505|
|Seifert, Stefanie; Sontheimer, Harald (2014) Bradykinin enhances invasion of malignant glioma into the brain parenchyma by inducing cells to undergo amoeboid migration. J Physiol 592:5109-27|
|Robert, Stephanie M; Ogunrinu-Babarinde, Toyin; Holt, Kenneth T et al. (2014) Role of glutamate transporters in redox homeostasis of the brain. Neurochem Int 73:181-91|
|Watkins, Stacey; Robel, Stefanie; Kimbrough, Ian F et al. (2014) Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 5:4196|
|Turner, Kathryn L; Honasoge, Avinash; Robert, Stephanie M et al. (2014) A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma. Glia 62:971-81|
Showing the most recent 10 out of 66 publications