Radiation Increases Functional KCa3.1 Expression and Invasiveness in Glioblastoma

Abstract

Glioblastoma (GBM) is a deadly brain tumor, with fast recurrence even after surgical intervention, radio- and chemotherapies. One of the reasons for relapse is the early invasion of surrounding brain parenchyma by GBM, rendering tumor eradication difficult. Recent studies demonstrate that, in addition to eliminate possible residual tumoral cells after surgery, radiation stimulates the infiltrative behavior of GBM cells. The intermediate conductance of Ca2+-activated potassium channels (KCa3.1) play an important role in regulating the migration of GBM. Here, we show that high dose radiation of patient-derived GBM cells increases their invasion, and induces the transcription of key genes related to these functions, including the IL-4/IL-4R pair. In addition, we demonstrate that radiation increases the expression of KCa3.1 channels, and that their pharmacological inhibition counteracts the pro-invasive phenotype induced by radiation in tumor cells. Our data describe a possible approach to treat tumor resistance that follows radiation therapy in GBM patients.

The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation

“…Here, we report that sublethal doses of irradiation enhance the motility and invasiveness of human GSCs through HIF1α nuclear accumulation that in turn increases the cytoplasmic actin nucleator JMY. Our study is thus in line with previous reports showing that ionizing radiation promotes migration and invasion in various cancer cell lines 15 , including human glioma cell lines 5 – 14 , 16 , 17 , 49 . However, to our knowledge, our study is the first to show not only that human GSCs are prone to this radiation effect, but also that this is specifically linked to their stemness properties, as radiation did not induce this effect on “differentiated” glioma cells.…”

“…However, to our knowledge, our study is the first to show not only that human GSCs are prone to this radiation effect, but also that this is specifically linked to their stemness properties, as radiation did not induce this effect on “differentiated” glioma cells. This link may explain why we were able to use a lower dose (0.5 Gy) to enhance GSC motility compared to the dose of 1 Gy 10 – 12 or greater 5 – 9 , 13 , 14 , 16 , 17 required to stimulate non-stem-like human glioma cell lines.…”

“…The highly infiltrative nature of GBM is thought to contribute to tumor relapse 4 . Moreover, ionizing radiation (1–20 Gy) has been shown to promote the migration and invasion of human glioblastoma cell lines in vitro 5 – 17 suggesting that this effect may allow some cancer cells to move away from the irradiated area, thereby reducing their radiation exposure at next irradiation sessions and overall the treatment efficacy.…”

KCa3.1 Channels Confer Radioresistance to Breast Cancer Cells

“…Since EMT was shown to precede tissue invasion and distant metastasis of carcinoma [38,39] including breast cancer [40], it is tempting to speculate that K Ca 3.1 promotes distant metastasis of breast cancer. Of note, ionizing radiation was demonstrated to stimulate migration of glioblastoma cells [21,31] by triggering signaling cascades that involve K Ca 3.1 [20]. The similarities between K Ca 3.1 channel function in glioblastoma and breast cancer might give rise to the speculation that K Ca 3.1 also promotes metastasis of irradiated breast cancer.…”

“…Besides chemotherapy, K Ca 3.1 has been implied to contribute to radioresistance of lung adenocarcinoma and glioblastoma [18,19]. Accordingly, pharmacological inhibition of K Ca 3.1 opposed the pro-migratory and pro-invasive behavior of patient-derived glioblastoma cells, which is frequently seen in radiation therapy-resistant tumors [20].…”