Temozolomide induces the expression of the glioma Big Potassium (gBK) ion channel, while inhibiting fascin-1 expression: possible targets for glioma therapy

ABSTRACT

Objective: Temozolomide (TMZ) improves Glioblastoma Multiforme (GBM) patient survival. The invasive behavior of the glioma cells is the cause of GBM relapse. The glioma BK ion channel (gBK) may provide glioma cells with a mechanism to invade surrounding tissue. gBK contains epitopes that cytolytic T lymphocytes (CTLs) can recognize and kill glioma cells. Fascin-1 is an actin crosslinking molecule that supports microvilli; these membrane protrusions provide a physical defense against CTLs. TMZ was investigated to determine its effect on gBK and fascin-1 expression.

Research design and methods: Human glioma cells cultured in TMZ were analyzed for their altered mRNA and gBK protein levels by using quantitative real time PCR, immunostaining and cellular functional assays.

Results: TMZ slowed glioma cell growth and inhibited their transmigratory properties due to loss of fascin-1. TMZ induced increased gBK and HLA expression and allowed these TMZ-treated cells to become better targets for gBK-specific CTLs.

Conclusions: Besides its traditional chemotherapeutic effect, TMZ can have four other targeted pathways: 1) slowed glioma cell growth; 2) inhibited glioma cell transmigration; 3) increased HLA-A2 and gBK tumor antigen production; 4) increased CTL-mediated cytolysis of the TMZ treated glioma cells due to the loss of their defensive membrane protrusions supported by fascin-1.

KEYWORDS:

• Cytolytic T lymphocytes
• fascin-1
• glioblastoma multiforme
• glioma BK ion channel
• microvilli
• real time PCR
• temozolomide
• TMZ

Declaration of interest

The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Funding

CA Kruse is funded by National Institutes of Health grants: [R01CA125244 and R01CA154256]. MR Janus was supported by a VA Merit Review.