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PKM2 subcellular localization is involved in oxaliplatin resistance acquisition in HT29 human colorectal cancer cell lines
Ginés Molina, Alba (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Bystrup, Sara (Institut Germans Trias i Pujol)
Ruiz de Porras, Vicenç (Institut Germans Trias i Pujol)
Guardia, Cristina (Institut Germans Trias i Pujol)
Musulén Palet, Eva (Institut Germans Trias i Pujol)
Martínez Cardús, Anna (Institut Germans Trias i Pujol)
Manzano, José Luis (Institut Germans Trias i Pujol)
Layos, Laura (Institut Germans Trias i Pujol)
Abad, Albert (Institut Germans Trias i Pujol)
Martínez Balibrea, Eva (Institut Germans Trias i Pujol)

Fecha: 2015
Resumen: Chemoresistance is the main cause of treatment failure in advanced colorectal cancer (CRC). However, molecular mechanisms underlying this phenomenon remain to be elucidated. In a previous work we identified low levels of PKM2 as a putative oxaliplatin-resistance marker in HT29 CRC cell lines and also in patients. In order to assess how PKM2 influences oxaliplatin response in CRC cells, we silenced PKM2 using specific siRNAs in HT29, SW480 and HCT116 cells. MTT test demonstrated that PKM2 silencing induced resistance in HT29 and SW480 cells and sensitivity in HCT116 cells. Same experiments in isogenic HCT116 p53 null cells and double silencing of p53 and PKM2 in HT29 cells failed to show an influence of p53. By using trypan blue stain and FITC-Annexin V/PI tests we detected that PKM2 knockdown was associated with an increase in cell viability but not with a decrease in apoptosis activation in HT29 cells. Fluorescence microscopy revealed PKM2 nuclear translocation in response to oxaliplatin in HCT116 and HT29 cells but not in OXA-resistant HTOXAR3 cells. Finally, by using a qPCR Array we demonstrated that oxaliplatin and PKM2 silencing altered cell death gene expression patterns including those of BMF, which was significantly increased in HT29 cells in response to oxaliplatin, in a dose and time-dependent manner, but not in siPKM2-HT29 and HTOXAR3 cells. BMF gene silencing in HT29 cells lead to a decrease in oxaliplatin-induced cell death. In conclusion, our data report new non-glycolytic roles of PKM2 in response to genotoxic damage and proposes BMF as a possible target gene of PKM2 to be involved in oxaliplatin response and resistance in CRC cells.
Nota: Ajuts: Beca bianual de la Fundació Olga Torres 2008-2009
Derechos: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Lengua: Anglès
Documento: article ; recerca ; publishedVersion
Materia: HT29 cells ; Apoptosis ; Gene expression ; Cell death ; Gene silencing ; Colorectal cancer ; Small interfering RNAs ; SW480 cells
Publicado en: PloS one, Vol. 10, No. 5 (May 2015) , p. e0123830, ISSN 1932-6203

DOI: 10.1371/journal.pone.0123830
PMID: 25955657

20 p, 10.3 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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 Registro creado el 2016-06-27, última modificación el 2021-04-08

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