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Full-Text Articles in Medicine and Health Sciences
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.
Dna-Pkcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression And Metastasis., Jonathan F Goodwin, Vishal Kothari, Justin M Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher Mcnair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen
Dna-Pkcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression And Metastasis., Jonathan F Goodwin, Vishal Kothari, Justin M Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher Mcnair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen
Department of Cancer Biology Faculty Papers
Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver …