The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment.
E2F1 is responsible for the regulation of FOXM1 expression, which plays a key role in epirubicin resistance. Here, we examined the role and regulation of E2F1 in response to epirubicin in cancer cells. We first showed that E2F1 plays a key role in promoting FOXM1 expression, cell survival, and epirubicin resistance as its depletion by siRNA attenuated FOXM1 induction and cell viability in response to epirubicin. We also found that the p38-MAPK activity mirrors the expression patterns of E2F1 and FOXM1 in both epirubicin-sensitive and -resistant MCF-7 breast cancer cells, suggesting that p38 has a role in regulating E2F1 expression and epirubicin resistance. Consistently, studies using pharmacologic inhibitors, siRNA knockdown, and knockout mouse embryonic fibroblasts (MEF) revealed that p38 mediates the E2F1 induction by epirubicin and that the induction of E2F1 by p38 is, in turn, mediated through its downstream kinase MK2 [mitogen-activated protein kinase (MAPK)-activated protein kinase 2; MAPKAPK2]. In agreement, in vitro phosphorylation assays showed that MK2 can directly phosphorylate E2F1 at Ser-364. Transfection assays also showed that E2F1 phosphorylation at Ser-364 participates in its induction by epirubicin but also suggests that other phosphorylation events are also involved. In addition, the p38-MK2 axis can also limit c-jun-NH(2)-kinase (JNK) induction by epirubicin and, notably, JNK represses FOXM1 expression. Collectively, these findings underscore the importance of p38-MK2 signaling in the control of E2F1 and FOXM1 expression as well as epirubicin sensitivity.
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
Natalia
N
de Olano
Chuay-Yeng
CY
Koo
Lara J
LJ
Monteiro
Paola H
PH
Pinto
Ana R
AR
Gomes
Rosa
R
Aligue
Eric W-F
EW
Lam
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015251:Epirubicin / Q000494:pharmacology*; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors; D015251:Epirubicin; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C493753:E2F1 protein, human; C107585:FOXM1 protein, human; C432165:pyrazolanthrone; C093642:SB 203580