Sökning: WFRF:(Lehto J) > PFKFB3 Inhibition S...
Fältnamn | Indikatorer | Metadata |
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000 | 02810naa a2200397 4500 | |
001 | oai:prod.swepub.kib.ki.se:147131054 | |
003 | SwePub | |
008 | 240701s2021 | |||||||||||000 ||eng| | |
024 | 7 | a http://kipublications.ki.se/Default.aspx?queryparsed=id:1471310542 URI |
024 | 7 | a https://doi.org/10.3390/cancers131436042 DOI |
040 | a (SwePub)ki | |
041 | a engb eng | |
042 | 9 SwePub | |
072 | 7 | a ref2 swepub-contenttype |
072 | 7 | a art2 swepub-publicationtype |
100 | 1 | a Ninou, AH4 aut |
245 | 1 0 | a PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair |
264 | c 2021-07-18 | |
264 | 1 | b MDPI AG,c 2021 |
520 | a Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments. | |
700 | 1 | a Lehto, J4 aut |
700 | 1 | a Chioureas, D4 aut |
700 | 1 | a Stigsdotter, Hu Karolinska Institutet4 aut |
700 | 1 | a Schelzig, K4 aut |
700 | 1 | a Akerlund, E4 aut |
700 | 1 | a Gudoityte, Gu Karolinska Institutet4 aut |
700 | 1 | a Joneborg, Uu Karolinska Institutet4 aut |
700 | 1 | a Carlson, J4 aut |
700 | 1 | a Jonkers, J4 aut |
700 | 1 | a Seashore-Ludlow, Bu Karolinska Institutet4 aut |
700 | 1 | a Gustafsson, NMS4 aut |
710 | 2 | a Karolinska Institutet4 org |
773 | 0 | t Cancersd : MDPI AGg 13:14q 13:14x 2072-6694 |
856 | 4 | u https://www.mdpi.com/2072-6694/13/14/3604/pdf |
856 | 4 8 | u http://kipublications.ki.se/Default.aspx?queryparsed=id:147131054 |
856 | 4 8 | u https://doi.org/10.3390/cancers13143604 |
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