UCP2 inhibition induces ROS/Akt/mTOR axis: role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism
| العنوان: | UCP2 inhibition induces ROS/Akt/mTOR axis: role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism |
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| المؤلفون: | Ivana Cataldo, Stefano Bruno, Massimo Donadelli, Elisa Dalla Pozza, Marta Palmieri, Raffaella Pacchiana, Michele Caraglia, Anna Grimaldi, Ilaria Dando, Paola Conti, Aldo Scarpa, Marco Cordani, Giovanna Butera |
| المساهمون: | Università degli Studi di Verona, Associazione Italiana per la Ricerca sul Cancro, Fondazione Umberto Veronesi, Dando, I, Pacchiana, R, Pozza, Ed, Cataldo, I, Bruno, S, Conti, P, Cordani, M, Grimaldi, A, Butera, G, Caraglia, M, Scarpa, A, Palmieri, M, Donadelli, M. |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Apoptosis, Pharmacology, Biochemistry, chemistry.chemical_compound, Iridoids, Uncoupling Protein 2, Pancreas cancer, GAPDH, TOR Serine-Threonine Kinases, Glyceraldehyde-3-Phosphate Dehydrogenases, Protein Transport, Everolimu, cell death, mTOR, Female, Carcinoma, Pancreatic Ductal, Signal Transduction, medicine.drug, Cell death, UCP2, Programmed cell death, uncoupling proteins, Antineoplastic Agents, everolimus, pancreas cancer, Biology, 03 medical and health sciences, Cell Line, Tumor, Physiology (medical), Uncoupling protein, medicine, Humans, Everolimus, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, Cell growth, RPTOR, Autophagy, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, 030104 developmental biology, chemistry, Genipin, Uncoupling proteins, Reactive Oxygen Species, Proto-Oncogene Proteins c-akt |
| الوصف: | Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear translocation of GAPDH. Caspase-mediated apoptosis by genipin and everolimus is further potentiated by the autophagy inhibitor 3-methyladenine revealing a protective role for Beclin1-mediated autophagy induced by the treatment. Mice xenograft of pancreatic adenocarcinoma further confirmed the antiproliferative outcome of drug combination without toxic effects for animals. Tumor masses from mice injected with UCP2 and mTOR inhibitors revealed a strong reduction in tumor volume and number of mitosis associated with a marked GAPDH nuclear positivity. Altogether, these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation and support the combined inhibition of UCP2 and of Akt/mTOR pathway as a novel therapeutic strategy in the treatment of pancreatic adenocarcinoma. This work was supported by Joint Projects program 2015 from University of Verona to M. Donadelli (no. B12I15002320003) and by Associazione Italiana Ricerca Cancro (AIRC 12182) to A. Scarpa. Ilaria Dando is a fellow of Fondazione Umberto Veronesi. Elisa Dalla Pozza is a fellow of AIRC 5 per mille (Grant no. 12182). |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e289bf69b5d40f28cad55bee3ac1d86Test http://hdl.handle.net/11562/969114Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2e289bf69b5d40f28cad55bee3ac1d86 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |