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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Main Authors: Euan A. Stronach, Michelle Chen, Elaina N. Maginn, Roshan Agarwal, Gordon B. Mills, Harpreet Wasan, Hani Gabra
Format: Article
Language:English
Published: Elsevier 2011-11-01
Series:Neoplasia: An International Journal for Oncology Research
Online Access:http://www.sciencedirect.com/science/article/pii/S147655861180093X
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spelling 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.
url http://www.sciencedirect.com/science/article/pii/S147655861180093X
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