Protein tyrosine phosphatome metabolic screen identifies TC‐PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics
| العنوان: | Protein tyrosine phosphatome metabolic screen identifies TC‐PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics |
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| المؤلفون: | Michel L. Tremblay, Serge Hardy, Noriko Uetani, Isabelle Aubry, Valerie Vinette, Hayley Insull |
| المصدر: | The FASEB Journal. 35 |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | STAT3 Transcription Factor, 0301 basic medicine, Protein tyrosine phosphatase, Mitochondrion, Mitochondrial Dynamics, Biochemistry, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, Genetics, Humans, Gene silencing, Phosphorylation, RNA, Small Interfering, Tyrosine, Molecular Biology, Cell Proliferation, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Chemistry, Protein-Tyrosine Kinases, HCT116 Cells, Cell biology, enzymes and coenzymes (carbohydrates), HEK293 Cells, 030104 developmental biology, Cancer cell, Energy Metabolism, Flux (metabolism), Tyrosine kinase, 030217 neurology & neurosurgery, Signal Transduction, Biotechnology |
| الوصف: | Metabolic reprogramming occurs in cancer cells and is regulated partly by the opposing actions of tyrosine kinases and tyrosine phosphatases. Several members of the protein tyrosine phosphatase (PTP) superfamily have been linked to cancer as either pro-oncogenic or tumor-suppressive enzymes. In order to investigate which PTPs can modulate the metabolic state of cancer cells, we performed an shRNA screen of PTPs in HCT116 human colorectal cancer cells. Among the 72 PTPs efficiently targeted, 24 were found to regulate mitochondrial respiration, 8 as negative and 16 as positive regulators. Of the latter, we selected TC-PTP (PTPN2) for further characterization since inhibition of this PTP resulted in major functional defects in oxidative metabolism without affecting glycolytic flux. Transmission electron microscopy revealed an increase in the number of damaged mitochondria in TC-PTP-null cells, demonstrating the potential role of this PTP in regulating mitochondrial homeostasis. Downregulation of STAT3 by siRNA-mediated silencing partially rescued the mitochondrial respiration defect observed in TC-PTP-deficient cells, supporting the role of this signaling axis in regulating mitochondrial activity. In addition, mitochondrial stress prevented an increased expression of electron transport chain-related genes in cells with TC-PTP silencing, correlating with decreased ATP production, cellular proliferation, and migration. Our shRNA-based metabolic screen revealed that PTPs can serve as either positive or negative regulators of cancer cell metabolism. Taken together, our findings uncover a new role for TC-PTP as an activator of mitochondrial metabolism, validating this PTP as a key target for cancer therapeutics. |
| تدمد: | 1530-6860 0892-6638 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::98b0cdbb4ca83292a8fce271ca0eda94 https://doi.org/10.1096/fj.202100207r |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....98b0cdbb4ca83292a8fce271ca0eda94 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15306860 08926638 |
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