PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses
| العنوان: | PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses |
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| المؤلفون: | Deok-Beom Jung, Debarshi Roy, Ling Jin, Julian R. Molina, Sayantani Sarkar Bhattacharya, Prabhu Thirusangu, Julie Staub, Viji Shridhar, Bhaskar Roy, Yinan Xiao |
| المصدر: | Cell Death & Disease Cell Death and Disease, Vol 10, Iss 10, Pp 1-16 (2019) |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Mesothelioma, Cancer Research, Programmed cell death, Lung Neoplasms, Phosphofructokinase-2, Pyridines, Pleural Neoplasms, Immunology, Mice, Nude, Apoptosis, Vacuole, medicine.disease_cause, Article, Cellular and Molecular Neuroscience, Mice, Calnexin, Cell Line, Tumor, medicine, Animals, Humans, lcsh:QH573-671, Cell Proliferation, lcsh:Cytology, Chemistry, Pinocytosis, Endoplasmic reticulum, Cell Cycle, Mesothelioma, Malignant, Cell Biology, Nutrient signalling, Cellular Reprogramming, Endoplasmic Reticulum Stress, Cell biology, Cancer cell, Unfolded protein response, Heterografts, Calcium, Female, Carcinogenesis, Glycolysis |
| الوصف: | The metabolic signatures of cancer cells are often associated with elevated glycolysis. Pharmacological (PFK158 treatment) and genetic inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a critical control point in the glycolytic pathway, decreases glucose uptake, ATP production, and lactate dehydrogenase activity and arrests malignant pleural mesothelioma (MPM) cells in the G0/G1 phase to induce cell death. To overcome this nutrient stress, inhibition of PFKFB3 activity led to an escalation in endoplasmic reticulum (ER) activity and aggravated ER stress mostly by upregulating BiP and GADD153 expression and activation of the endocytic Rac1-Rab5-Rab7 pathway resulting in a unique form of cell death called “methuosis” in both the sarcomatoid (H28) and epithelioid (EMMeso) cells. Transmission electron microscopy (TEM) analysis showed the formation of nascent macropinocytotic vesicles, which rapidly coalesced to form large vacuoles with compromised lysosomal function. Both immunofluorescence microscopy and co-immunoprecipitation analyses revealed that upon PFKFB3 inhibition, two crucial biomolecules of each pathway, Rac1 and Calnexin interact with each other. Finally, PFK158 alone and in combination with carboplatin-inhibited tumorigenesis of EMMeso xenografts in vivo. Since most cancer cells exhibit an increased glycolytic rate, these results provide evidence for PFK158, in combination with standard chemotherapy, may have a potential in the treatment of MPM. |
| تدمد: | 2041-4889 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::849a791d237451423bf4b4858c3b8e41Test https://pubmed.ncbi.nlm.nih.gov/31562297Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....849a791d237451423bf4b4858c3b8e41 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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