DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance
Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS) ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rate...
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doaj-608e1dfca44347598c179e0c7d2eced02020-11-25T00:16:22ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022011-11-0113111069108010.1593/neo.111032DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum ResistanceEuan A. Stronach0Michelle Chen1Elaina N. Maginn2Roshan Agarwal3Gordon B. Mills4Harpreet Wasan5Hani Gabra6Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London London UKOvarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London London UKOvarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London London UKOvarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London London UKThe University of Texas MD Anderson Cancer Center Houston TX USAOvarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London London UKOvarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London London UK Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS) ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinumresistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK), and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Re-sensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulin-mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage–mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors. http://www.sciencedirect.com/science/article/pii/S147655861180093X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Euan A. Stronach Michelle Chen Elaina N. Maginn Roshan Agarwal Gordon B. Mills Harpreet Wasan Hani Gabra |
spellingShingle |
Euan A. Stronach Michelle Chen Elaina N. Maginn Roshan Agarwal Gordon B. Mills Harpreet Wasan Hani Gabra DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance Neoplasia: An International Journal for Oncology Research |
author_facet |
Euan A. Stronach Michelle Chen Elaina N. Maginn Roshan Agarwal Gordon B. Mills Harpreet Wasan Hani Gabra |
author_sort |
Euan A. Stronach |
title |
DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance |
title_short |
DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance |
title_full |
DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance |
title_fullStr |
DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance |
title_full_unstemmed |
DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance |
title_sort |
dna-pk mediates akt activation and apoptosis inhibition in clinically acquired platinum resistance |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 1522-8002 |
publishDate |
2011-11-01 |
description |
Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS) ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinumresistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK), and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Re-sensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulin-mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage–mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.
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url |
http://www.sciencedirect.com/science/article/pii/S147655861180093X |
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