Aurora kinase inhibition downregulates NF-kappaB and sensitises tumour cells to chemotherapeutic agents.
We have identified that Aurora-A activates NF-kappaB via IkappaBalpha phosphorylation. Here, we analysed different human tumour cell types for their NF-kappaB activity. We found that there is an association between cell resistance to chemotherapeutic agents and NF-kappaB activation. A549 human lung adenocarcinoma cells and SKOV3 human ovarian cancer cells have high levels of NF-kappaB and are resistant to cytotoxic agents such as adriamycin and VP-16 (etoposide). We also found that in A549 and SKOV3 cells treated with a small molecule inhibitor towards Aurora kinases, the NF-kappaB activity was downregulated and the efficacy of cytotoxic drugs was enhanced. In addition, the transcriptional targets Bcl-XL and Bcl-2 were downregulated. This study provides evidence for a potential mechanism of chemoresistance and may be useful for the enhancement of certain chemotherapeutics regimens.
Sun
Chongbo
C
Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK, Belmont, Surrey SM2 5NG, UK.
Chan
Florence
F
Briassouli
Paraskevi
P
Linardopoulos
Spiros
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D000970:Antineoplastic Agents; D064127:Aurora Kinases; D016328:NF-kappa B; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines