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1.
Eur Biophys J ; 45(7): 585-598, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27165704

ABSTRACT

K+ channels crosstalk with biochemical signaling cascades and regulate virtually all cellular processes by adjusting the intracellular K+ concentration, generating the membrane potential, mediating cell volume changes, contributing to Ca2+ signaling, and directly interacting within molecular complexes with membrane receptors and downstream effectors. Tumor cells exhibit aberrant expression and activity patterns of K+ channels. The upregulation of highly "oncogenic" K+ channels such as the Ca2+-activated IK channel may drive the neoplastic transformation, malignant progression, metastasis, or therapy resistance of tumor cells. In particular, ionizing radiation in doses used for fractionated radiotherapy in the clinic has been shown to activate K+ channels. Radiogenic K+ channel activity, in turn, contributes to the DNA damage response and promotes survival of the irradiated tumor cells. Tumor-specific overexpression of certain K+ channel types together with the fact that pharmacological K+ channel modulators are already in clinical use or well tolerated in clinical trials suggests that K+ channel targeting alone or in combination with radiotherapy might become a promising new strategy of anti-cancer therapy. The present article aims to review our current knowledge on K+ channel signaling in irradiated tumor cells. Moreover, it provides new data on molecular mechanisms of radiogenic K+ channel activation and downstream signaling events.


Subject(s)
Neoplasms/pathology , Neoplasms/radiotherapy , Potassium Channels/metabolism , Signal Transduction/radiation effects , Animals , Humans , Neoplasms/metabolism
2.
Oncotarget ; 8(56): 95896-95913, 2017 Nov 10.
Article in English | MEDLINE | ID: mdl-29221175

ABSTRACT

TRPM8 is a Ca2+-permeable nonselective cation channel belonging to the melastatin sub-group of the transient receptor potential (TRP) family. TRPM8 is aberrantly overexpressed in a variety of tumor entities including glioblastoma multiforme where it reportedly contributes to tumor invasion. The present study aimed to disclose further functions of TRPM8 in glioma biology in particular upon cell injury by ionizing radiation. To this end, TCGA data base was queried to expose the TRPM8 mRNA abundance in human glioblastoma specimens and immunoblotting was performed to analyze the TRPM8 protein abundance in primary cultures of human glioblastoma. Moreover, human glioblastoma cell lines were irradiated with 6 MV photons and TRPM8 channels were targeted pharmacologically or by RNA interference. TRPM8 abundance, Ca2+ signaling and resulting K+ channel activity, chemotaxis, cell migration, clonogenic survival, DNA repair, apoptotic cell death, and cell cycle control were determined by qRT-PCR, fura-2 Ca2+ imaging, patch-clamp recording, transfilter migration assay, wound healing assay, colony formation assay, immunohistology, flow cytometry, and immunoblotting. As a result, human glioblastoma upregulates TRPM8 channels to variable extent. TRPM8 inhibition or knockdown slowed down cell migration and chemotaxis, attenuated DNA repair and clonogenic survival, triggered apoptotic cell death, impaired cell cycle and radiosensitized glioblastoma cells. Mechanistically, ionizing radiation activated and upregulated TRPM8-mediated Ca2+ signaling that interfered with cell cycle control probably via CaMKII, cdc25C and cdc2. Combined, our data suggest that TRPM8 channels contribute to spreading, survival and radioresistance of human glioblastoma and, therefore, might represent a promising target in future anti-glioblastoma therapy.

3.
Sci Rep ; 7(1): 12423, 2017 09 29.
Article in English | MEDLINE | ID: mdl-28963552

ABSTRACT

Radiation is a highly efficient therapy in squamous head and neck carcinoma (HNSCC) treatment. However, local recurrence and metastasis are common complications. Recent evidence shows that cancer-cell-derived exosomes modify tumour cell movement and metastasis. In this study, we link radiation-induced changes of exosomes to their ability to promote migration of recipient HNSCC cells. We demonstrate that exosomes isolated from irradiated donor cells boost the motility of the HNSCC cells BHY and FaDu. Molecular data identified enhanced AKT-signalling, manifested through increased phospho-mTOR, phospho-rpS6 and MMP2/9 protease activity, as underlying mechanism. AKT-inhibition blocked the pro-migratory action, suggesting AKT-signalling as key player in exosome-mediated migration. Proteomic analysis of exosomes isolated from irradiated and non-irradiated BHY donor cells identified 39 up- and 36 downregulated proteins. In line with the observed pro-migratory effect of exosomes isolated from irradiated cells protein function analysis assigned the deregulated exosomal proteins to cell motility and AKT-signalling. Together, our findings demonstrate that exosomes derived from irradiated HNSCC cells confer a migratory phenotype to recipient cancer cells. This is possibly due to radiation-regulated exosomal proteins that increase AKT-signalling. We conclude that exosomes may act as driver of HNSCC progression during radiotherapy and are therefore attractive targets to improve radiation therapy strategies.


Subject(s)
Cell Movement/radiation effects , Exosomes , Head and Neck Neoplasms , Proto-Oncogene Proteins c-akt/metabolism , Squamous Cell Carcinoma of Head and Neck , TOR Serine-Threonine Kinases/metabolism , Cell Line, Tumor , Exosomes/metabolism , Exosomes/radiation effects , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/radiotherapy , Humans , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Proteomics , Ribosomal Protein S6/metabolism , Signal Transduction , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/radiotherapy
4.
Oncotarget ; 7(12): 14259-78, 2016 Mar 22.
Article in English | MEDLINE | ID: mdl-26893360

ABSTRACT

Infiltration of the brain by glioblastoma cells reportedly requires Ca2+ signals and BK K+ channels that program and drive glioblastoma cell migration, respectively. Ionizing radiation (IR) has been shown to induce expression of the chemokine SDF-1, to alter the Ca2+ signaling, and to stimulate cell migration of glioblastoma cells. Here, we quantified fractionated IR-induced migration/brain infiltration of human glioblastoma cells in vitro and in an orthotopic mouse model and analyzed the role of SDF-1/CXCR4 signaling and BK channels. To this end, the radiation-induced migratory phenotypes of human T98G and far-red fluorescent U-87MG-Katushka glioblastoma cells were characterized by mRNA and protein expression, fura-2 Ca2+ imaging, BK patch-clamp recording and transfilter migration assay. In addition, U-87MG-Katushka cells were grown to solid glioblastomas in the right hemispheres of immunocompromised mice, fractionated irradiated (6 MV photons) with 5 × 0 or 5 × 2 Gy, and SDF-1, CXCR4, and BK protein expression by the tumor as well as glioblastoma brain infiltration was analyzed in dependence on BK channel targeting by systemic paxilline application concomitant to IR. As a result, IR stimulated SDF-1 signaling and induced migration of glioblastoma cells in vitro and in vivo. Importantly, paxilline blocked IR-induced migration in vivo. Collectively, our data demonstrate that fractionated IR of glioblastoma stimulates and BK K+ channel targeting mitigates migration and brain infiltration of glioblastoma cells in vivo. This suggests that BK channel targeting might represent a novel approach to overcome radiation-induced spreading of malignant brain tumors during radiotherapy.


Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/pathology , Cell Movement/radiation effects , Glioblastoma/pathology , Large-Conductance Calcium-Activated Potassium Channels/metabolism , Animals , Apoptosis/radiation effects , Brain Neoplasms/metabolism , Brain Neoplasms/radiotherapy , Cell Proliferation/radiation effects , Chemokine CXCL12/metabolism , Female , Glioblastoma/metabolism , Glioblastoma/radiotherapy , Humans , Large-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Radiation, Ionizing , Receptors, CXCR4/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
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