Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomasCitation formats

  • External authors:
  • Natalie Burrows
  • Joseph Williams
  • Brian Telfer
  • Julia Resch
  • Helen Valentine
  • Richard Fitzmaurice
  • Amanda Eustace
  • Joely Irlam
  • Cuong Hoang-Vu
  • Georg Brabant

Standard

Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas. / Burrows, Natalie; Williams, Joseph; Telfer, Brian; Resch, Julia; Valentine, Helen; Fitzmaurice, Richard; Eustace, Amanda; Irlam, Joely; Rowling, Emily; Hoang-Vu, Cuong; West, Catharine; Brabant, Georg; Williams, Kaye.

In: Oncotarget, Vol. 7, No. 39, 04.08.2016, p. 63106-63123.

Research output: Contribution to journalArticlepeer-review

Harvard

Burrows, N, Williams, J, Telfer, B, Resch, J, Valentine, H, Fitzmaurice, R, Eustace, A, Irlam, J, Rowling, E, Hoang-Vu, C, West, C, Brabant, G & Williams, K 2016, 'Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas', Oncotarget, vol. 7, no. 39, pp. 63106-63123. https://doi.org/10.18632/oncotarget.11056

APA

Burrows, N., Williams, J., Telfer, B., Resch, J., Valentine, H., Fitzmaurice, R., Eustace, A., Irlam, J., Rowling, E., Hoang-Vu, C., West, C., Brabant, G., & Williams, K. (2016). Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas. Oncotarget, 7(39), 63106-63123. https://doi.org/10.18632/oncotarget.11056

Vancouver

Burrows N, Williams J, Telfer B, Resch J, Valentine H, Fitzmaurice R et al. Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas. Oncotarget. 2016 Aug 4;7(39):63106-63123. https://doi.org/10.18632/oncotarget.11056

Author

Burrows, Natalie ; Williams, Joseph ; Telfer, Brian ; Resch, Julia ; Valentine, Helen ; Fitzmaurice, Richard ; Eustace, Amanda ; Irlam, Joely ; Rowling, Emily ; Hoang-Vu, Cuong ; West, Catharine ; Brabant, Georg ; Williams, Kaye. / Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas. In: Oncotarget. 2016 ; Vol. 7, No. 39. pp. 63106-63123.

Bibtex

@article{e496ba0b6f504195b0490f70bf37b873,
title = "Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas",
abstract = "Anaplastic (ATC) and certain follicular thyroid-carcinomas (FTCs) are radioresistant. The Phosphatidylinositide 3-kinase (PI3K) pathway is commonly hyperactivated in thyroid-carcinomas. PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation: How PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas is unknown. Further uncertainties exist in how these interactions function under the radioresistant hypoxic microenvironment.Under normoxia/anoxia, ATC (8505c) and FTC (FTC-133) cells were irradiated, with PI3K-inhibition (via GDC-0941 and PTEN-reconstitution into PTEN-null FTC-133s) and effects on PIKK-activation, DNA-damage, clonogenic-survival and cell cycle, assessed. FTC-xenografts were treated with 5 × 2 Gy, ± 50 mg/kg GDC-0941 (twice-daily; orally) for 14 days and PIKK-activation and tumour-growth assessed. PIKK-expression was additionally assessed in 12 human papillary thyroid-carcinomas, 13 FTCs and 12 ATCs.GDC-0941 inhibited radiation-induced activation of Ataxia-telangiectasia mutated (ATM), ATM-and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inhibition of ATM and DNA-PKcs was PI3K-dependent, since activation was reduced in PTEN-reconstituted FTC-133s. Inhibition of PIKK-activation was greater under anoxia: Consequently, whilst DNA-damage was increased and prolonged under both normoxia and anoxia, PI3K-inhibition only reduced clonogenic-survival under anoxia. GDC-0941 abrogated radiation-induced cell cycle arrest, an effect most likely linked to the marked inhibition of ATR-activation. Importantly, GDC-0941 inhibited radiation-induced PIKK-activation in FTC-xenografts leading to a significant increase in time taken for tumours to triple in size: 26.5 ± 5 days (radiation-alone) versus 31.5 ± 5 days (dual-treatment). PIKKs were highly expressed across human thyroid-carcinoma classifications, with ATM scoring consistently lower. Interestingly, some loss of ATM and DNA-PKcs was observed. These data provide new insight into the mechanisms of hypoxia-associated radioresistance in thyro{id-carcinoma.",
author = "Natalie Burrows and Joseph Williams and Brian Telfer and Julia Resch and Helen Valentine and Richard Fitzmaurice and Amanda Eustace and Joely Irlam and Emily Rowling and Cuong Hoang-Vu and Catharine West and Georg Brabant and Kaye Williams",
year = "2016",
month = aug,
day = "4",
doi = "10.18632/oncotarget.11056",
language = "English",
volume = "7",
pages = "63106--63123",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "39",

}

RIS

TY - JOUR

T1 - Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas

AU - Burrows, Natalie

AU - Williams, Joseph

AU - Telfer, Brian

AU - Resch, Julia

AU - Valentine, Helen

AU - Fitzmaurice, Richard

AU - Eustace, Amanda

AU - Irlam, Joely

AU - Rowling, Emily

AU - Hoang-Vu, Cuong

AU - West, Catharine

AU - Brabant, Georg

AU - Williams, Kaye

PY - 2016/8/4

Y1 - 2016/8/4

N2 - Anaplastic (ATC) and certain follicular thyroid-carcinomas (FTCs) are radioresistant. The Phosphatidylinositide 3-kinase (PI3K) pathway is commonly hyperactivated in thyroid-carcinomas. PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation: How PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas is unknown. Further uncertainties exist in how these interactions function under the radioresistant hypoxic microenvironment.Under normoxia/anoxia, ATC (8505c) and FTC (FTC-133) cells were irradiated, with PI3K-inhibition (via GDC-0941 and PTEN-reconstitution into PTEN-null FTC-133s) and effects on PIKK-activation, DNA-damage, clonogenic-survival and cell cycle, assessed. FTC-xenografts were treated with 5 × 2 Gy, ± 50 mg/kg GDC-0941 (twice-daily; orally) for 14 days and PIKK-activation and tumour-growth assessed. PIKK-expression was additionally assessed in 12 human papillary thyroid-carcinomas, 13 FTCs and 12 ATCs.GDC-0941 inhibited radiation-induced activation of Ataxia-telangiectasia mutated (ATM), ATM-and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inhibition of ATM and DNA-PKcs was PI3K-dependent, since activation was reduced in PTEN-reconstituted FTC-133s. Inhibition of PIKK-activation was greater under anoxia: Consequently, whilst DNA-damage was increased and prolonged under both normoxia and anoxia, PI3K-inhibition only reduced clonogenic-survival under anoxia. GDC-0941 abrogated radiation-induced cell cycle arrest, an effect most likely linked to the marked inhibition of ATR-activation. Importantly, GDC-0941 inhibited radiation-induced PIKK-activation in FTC-xenografts leading to a significant increase in time taken for tumours to triple in size: 26.5 ± 5 days (radiation-alone) versus 31.5 ± 5 days (dual-treatment). PIKKs were highly expressed across human thyroid-carcinoma classifications, with ATM scoring consistently lower. Interestingly, some loss of ATM and DNA-PKcs was observed. These data provide new insight into the mechanisms of hypoxia-associated radioresistance in thyro{id-carcinoma.

AB - Anaplastic (ATC) and certain follicular thyroid-carcinomas (FTCs) are radioresistant. The Phosphatidylinositide 3-kinase (PI3K) pathway is commonly hyperactivated in thyroid-carcinomas. PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation: How PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas is unknown. Further uncertainties exist in how these interactions function under the radioresistant hypoxic microenvironment.Under normoxia/anoxia, ATC (8505c) and FTC (FTC-133) cells were irradiated, with PI3K-inhibition (via GDC-0941 and PTEN-reconstitution into PTEN-null FTC-133s) and effects on PIKK-activation, DNA-damage, clonogenic-survival and cell cycle, assessed. FTC-xenografts were treated with 5 × 2 Gy, ± 50 mg/kg GDC-0941 (twice-daily; orally) for 14 days and PIKK-activation and tumour-growth assessed. PIKK-expression was additionally assessed in 12 human papillary thyroid-carcinomas, 13 FTCs and 12 ATCs.GDC-0941 inhibited radiation-induced activation of Ataxia-telangiectasia mutated (ATM), ATM-and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inhibition of ATM and DNA-PKcs was PI3K-dependent, since activation was reduced in PTEN-reconstituted FTC-133s. Inhibition of PIKK-activation was greater under anoxia: Consequently, whilst DNA-damage was increased and prolonged under both normoxia and anoxia, PI3K-inhibition only reduced clonogenic-survival under anoxia. GDC-0941 abrogated radiation-induced cell cycle arrest, an effect most likely linked to the marked inhibition of ATR-activation. Importantly, GDC-0941 inhibited radiation-induced PIKK-activation in FTC-xenografts leading to a significant increase in time taken for tumours to triple in size: 26.5 ± 5 days (radiation-alone) versus 31.5 ± 5 days (dual-treatment). PIKKs were highly expressed across human thyroid-carcinoma classifications, with ATM scoring consistently lower. Interestingly, some loss of ATM and DNA-PKcs was observed. These data provide new insight into the mechanisms of hypoxia-associated radioresistance in thyro{id-carcinoma.

U2 - 10.18632/oncotarget.11056

DO - 10.18632/oncotarget.11056

M3 - Article

C2 - 27527858

VL - 7

SP - 63106

EP - 63123

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 39

ER -