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  1. Article ; Online: Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer

    Zoltán Pethő / Karolina Najder / Stephanie Beel / Benedikt Fels / Ilka Neumann / Sandra Schimmelpfennig / Sarah Sargin / Maria Wolters / Klavs Grantins / Eva Wardelmann / Miso Mitkovski / Andrea Oeckinghaus / Albrecht Schwab

    JCI Insight, Vol 8, Iss

    2023  Volume 19

    Abstract: Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and ...

    Abstract Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH was sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding, focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially altered the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreased when mice received the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifted from granulocyte rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.
    Keywords Metabolism ; Oncology ; Medicine ; R
    Subject code 500
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Orai3 Calcium Channel Regulates Breast Cancer Cell Migration through Calcium-Dependent and -Independent Mechanisms

    Mohamed Chamlali / Sana Kouba / Lise Rodat-Despoix / Luca Matteo Todesca / Zoltán Pethö / Albrecht Schwab / Halima Ouadid-Ahidouch

    Cells, Vol 10, Iss 3487, p

    2021  Volume 3487

    Abstract: Orai3 calcium (Ca 2+ ) channels are implicated in multiple breast cancer processes, such as proliferation and survival as well as resistance to chemotherapy. However, their involvement in the breast cancer cell migration processes remains vague. In the ... ...

    Abstract Orai3 calcium (Ca 2+ ) channels are implicated in multiple breast cancer processes, such as proliferation and survival as well as resistance to chemotherapy. However, their involvement in the breast cancer cell migration processes remains vague. In the present study, we exploited MDA-MB-231 and MDA-MB-231 BrM2 basal-like estrogen receptor-negative (ER − ) cell lines to assess the direct role of Orai3 in cell migration. We showed that Orai3 regulates MDA-MB-231 and MDA-MB-231 BrM2 cell migration in two distinct ways. First, we showed that Orai3 remodels cell adhesive capacities by modulating the intracellular Ca 2+ concentration. Orai3 silencing (siOrai3) decreased calpain activity, cell adhesion and migration in a Ca 2+ -dependent manner. In addition, Orai3 interacts with focal adhesion kinase (FAK) and regulates the actin cytoskeleton, in a Ca 2+ -independent way. Thus, siOrai3 modulates cell morphology by altering F-actin polymerization via a loss of interaction between Orai3 and FAK. To summarize, we demonstrated that Orai3 regulates cell migration through a Ca 2+ -dependent modulation of calpain activity and, in a Ca 2+ -independent manner, the actin cytoskeleton architecture via FAK.
    Keywords breast cancer ; Orai3 ; calcium ; cell migration ; cell adhesion ; calpain ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Multiple mechanisms contribute to fluorometry signals from the voltage-gated proton channel

    Ferenc Papp / Gilman E. S. Toombes / Zoltán Pethő / Adrienn Bagosi / Adam Feher / János Almássy / Jesús Borrego / Ákos Kuki / Sándor Kéki / Gyorgy Panyi / Zoltan Varga

    Communications Biology, Vol 5, Iss 1, Pp 1-

    2022  Volume 12

    Abstract: Fluorometry signals indicating conformational change in an ion channel are generated by quenching amino acids and lipid effects during movement of the dye relative to the plane of the membrane. ...

    Abstract Fluorometry signals indicating conformational change in an ion channel are generated by quenching amino acids and lipid effects during movement of the dye relative to the plane of the membrane.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Impact of the Nuclear Envelope on Malignant Transformation, Motility, and Survival of Lung Cancer Cells

    Sílvio Terra Stefanello / Isabelle Luchtefeld / Ivan Liashkovich / Zoltan Pethö / Ihab Azzam / Etmar Bulk / Gonzalo Rosso / Lilly Döhlinger / Bettina Hesse / Andrea Oeckinghaus / Victor Shahin

    Advanced Science, Vol 8, Iss 22, Pp n/a-n/a (2021)

    2021  

    Abstract: Abstract Nuclear pore complexes (NPCs) selectively mediate all nucleocytoplasmic transport and engage in fundamental cell‐physiological processes. It is hypothesized that NPCs are critical for malignant transformation and survival of lung cancer cells, ... ...

    Abstract Abstract Nuclear pore complexes (NPCs) selectively mediate all nucleocytoplasmic transport and engage in fundamental cell‐physiological processes. It is hypothesized that NPCs are critical for malignant transformation and survival of lung cancer cells, and test the hypothesis in lowly and highly metastatic non‐small human lung cancer cells (NSCLCs). It is shown that malignant transformation is paralleled by an increased NPCs density, and a balanced pathological weakening of the physiological stringency of the NPC barrier. Pharmacological interference using barrier‐breaking compounds collapses the stringency. Concomitantly, it induces drastic overall structural changes of NSCLCs, terminating their migration. Moreover, the degree of malignancy is found to be paralleled by substantially decreased lamin A/C levels. The latter provides crucial structural and mechanical stability to the nucleus, and interacts with NPCs, cytoskeleton, and nucleoskeleton for cell maintenance, survival, and motility. The recent study reveals the physiological importance of the NPC barrier stringency for mechanical and structural resilience of normal cell nuclei. Hence, reduced lamin A/C levels in conjunction with controlled pathological weakening of the NPC barrier stringency may facilitate deformability of NSCLCs during the metastasis steps. Modulation of the NPC barrier presents a potential strategy for suppressing the malignant phenotype or enhancing the effectiveness of currently existing chemotherapeutics.
    Keywords cancer ; cellular physiology and biophysics ; nanomedicine ; nuclear envelope ; nuclear pores ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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