Upregulation of Twist-1 by NF-kappaB blocks cytotoxicity induced by chemotherapeutic drugs.
NF-kappaB/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-kappaB blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-kappaB is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-kappaB has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-kappaB inhibits PCD triggered by chemotherapeutic drugs, however, remains poorly understood. To understand this mechanism, we sought to identify unrecognized protective genes that are regulated by NF-kappaB. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-kappaB. Twist-1 is an evolutionarily conserved target of NF-kappaB, blocks PCD induced by chemotherapeutic drugs and TNF-alpha in NF-kappaB-deficient cells, and is essential to counter this PCD in cancer cells. The protective activity of Twist-1 seemingly halts PCD independently of interference with cytotoxic JNK, p53, and p19(ARF) signaling, suggesting that it mediates a novel protective mechanism activated by NF-kappaB. Indeed, our data indicate that this activity involves a control of inhibitory Bcl-2 phosphorylation. The data also suggest that Twist-1 and -2 play an important role in NF-kappaB-dependent chemoresistance.
Pham
Can G
CG
The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, IL 60637, USA.
Bubici
Concetta
C
Zazzeroni
Francesca
F
Knabb
James R
JR
Papa
Salvatore
S
Kuntzen
Christian
C
Franzoso
Guido
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016328:NF-kappa B; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; C103173:TWIST1 protein, human; C486274:TWIST2 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051879:Twist-Related Protein 1; D003630:Daunorubicin