TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

Background: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase th...

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Vydáno v:British journal of cancer Ročník 117; číslo 4; s. 503 - 512
Hlavní autoři: Pirovano, Giacomo, Ashton, Thomas M, Herbert, Katharine J, Bryant, Richard J, Verrill, Clare L, Cerundolo, Lucia, Buffa, Francesca M, Prevo, Remko, Harrap, Iona, Ryan, Anderson J, Macaulay, Valentine, McKenna, William G, Higgins, Geoff S
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 08.08.2017
Nature Publishing Group
Témata:
631/45/607/275
692/4028/67/589/466
692/699/67/1059/485
Apoptosis
Apoptosis - drug effects
Apoptosis - radiation effects
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell cycle
Cell Cycle Checkpoints - drug effects
Cell Cycle Checkpoints - genetics
Cell Cycle Checkpoints - radiation effects
Cell death
Cell Line, Tumor
Cell Nucleus - genetics
Cell Nucleus - radiation effects
Chromosome aberrations
Chromosome Aberrations - drug effects
Chromosome Aberrations - radiation effects
DNA damage
Drug Resistance
Epidemiology
Gene Knockdown Techniques
HCT116 Cells
HeLa Cells
Humans
Kinases
Male
MAP kinase
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - genetics
Mitogen-Activated Protein Kinase Kinases - metabolism
Molecular Medicine
Neoplasm Recurrence, Local - metabolism
Oncology
Prostate cancer
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - radiotherapy
Protein kinase
Protein Kinase Inhibitors - pharmacology
Proteins
Quinolones - pharmacology
Radiation therapy
Radiation Tolerance - drug effects
Radiation Tolerance - genetics
Radiosensitivity
Side effects
Survival Rate
Translational Therapeutics
Tumor cell lines
Tumors
PBK
TOPK
cancer
radiosensitivity
ISSN:0007-0920, 1532-1827, 1532-1827
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Shrnutí:Background: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers. Methods: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy. Results: TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G 1 /S transition and G 2 /M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy. Conclusions: This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/bjc.2017.197