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Full-Text Articles in Medicine and Health Sciences
Mdm2 Is Required For Survival And Growth Of P53-Deficient Cancer Cells., Kyle P Feeley, Clare M. Adams, Ramkrishna Mitra, Christine M. Eischen
Mdm2 Is Required For Survival And Growth Of P53-Deficient Cancer Cells., Kyle P Feeley, Clare M. Adams, Ramkrishna Mitra, Christine M. Eischen
Department of Cancer Biology Faculty Papers
p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of Mdm2 in T-cell lymphomas or sarcomas lacking p53 induced apoptosis and G2 cell-cycle arrest, prolonging survival of mice with these tumors. p53-/- fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to pre-malignant cells. Mdm2 deletion in p53-/- cells upregulated p53 transcriptional target genes that induce apoptosis and cell-cycle arrest. Mdm2 deletion also increased levels of …
Mitochondrial Akt Regulation Of Hypoxic Tumor Reprogramming., Young Chan Chae, Valentina Vaira, M. Cecilia Caino, Hsin-Yao Tang, Jae Ho Seo, Andrew V. Kossenkov, Luisa Ottobrini, Cristina Martelli, Giovanni Lucignani, Irene Bertolini, Marco Locatelli, Kelly G. Bryant, Jagadish C. Ghosh, Sofia Lisanti, Bonsu Ku, Silvano Bosari, Lucia R. Languino, David W. Speicher, Dario C. Altieri
Mitochondrial Akt Regulation Of Hypoxic Tumor Reprogramming., Young Chan Chae, Valentina Vaira, M. Cecilia Caino, Hsin-Yao Tang, Jae Ho Seo, Andrew V. Kossenkov, Luisa Ottobrini, Cristina Martelli, Giovanni Lucignani, Irene Bertolini, Marco Locatelli, Kelly G. Bryant, Jagadish C. Ghosh, Sofia Lisanti, Bonsu Ku, Silvano Bosari, Lucia R. Languino, David W. Speicher, Dario C. Altieri
Department of Cancer Biology Faculty Papers
Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer.
Suppression Of Invasion And Metastasis Of Triple-Negative Breast Cancer Lines By Pharmacological Or Genetic Inhibition Of Slug Activity., Giovanna Ferrari-Amorotti, Claudia Chiodoni, Fei Shen, Sara Cattelani, Angela Rachele Soliera, Gloria Manzotti, Giulia Grisendi, Massimo Dominici, Francesco Rivasi, Mario Paolo Colombo, Alessandro Fatatis, Bruno Calabretta
Suppression Of Invasion And Metastasis Of Triple-Negative Breast Cancer Lines By Pharmacological Or Genetic Inhibition Of Slug Activity., Giovanna Ferrari-Amorotti, Claudia Chiodoni, Fei Shen, Sara Cattelani, Angela Rachele Soliera, Gloria Manzotti, Giulia Grisendi, Massimo Dominici, Francesco Rivasi, Mario Paolo Colombo, Alessandro Fatatis, Bruno Calabretta
Department of Cancer Biology Faculty Papers
Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic …