TY - JOUR
T1 - Mutant p53 Reprograms TNF Signaling in Cancer Cells through Interaction with the Tumor Suppressor DAB2IP
AU - Di Minin, Giulio
AU - Bellazzo, Arianna
AU - DalFerro, Marco
AU - Chiaruttini, Giulia
AU - Nuzzo, Simona
AU - Bicciato, Silvio
AU - Piazza, Silvano
AU - Rami, Damiano
AU - Bulla, Roberta
AU - Sommaggio, Roberta
AU - Rosato, Antonio
AU - DelSal, Giannino
AU - Collavin, Licio
PY - 2014/12/4
Y1 - 2014/12/4
N2 - Inflammation is a significant factor in cancer development, and a molecular understanding of the parameters dictating the impact of inflammation on cancers could significantly improve treatment. The tumor suppressor p53 is frequently mutated in cancer, and p53 missense mutants (mutp53) can acquire oncogenic properties. We report that cancer cells with mutp53 respond to inflammatory cytokines increasing their invasive behavior. Notably, this action is coupled to expression of chemokines that can expose the tumor to host immunity, potentially affecting response to therapy. Mechanistically, mutp53 fuels NF-κB activation while it dampens activation of ASK1/JNK by TNFα, and this action depends on mutp53 binding and inhibiting the tumor suppressor DAB2IP in the cytoplasm. Interfering with such interaction reduced aggressiveness of cancer cells in xenografts. This interaction is an unexplored mechanism by which mutant p53 can influence tumor evolution, with implications for our understanding of the complex role of inflammation in cancer.
AB - Inflammation is a significant factor in cancer development, and a molecular understanding of the parameters dictating the impact of inflammation on cancers could significantly improve treatment. The tumor suppressor p53 is frequently mutated in cancer, and p53 missense mutants (mutp53) can acquire oncogenic properties. We report that cancer cells with mutp53 respond to inflammatory cytokines increasing their invasive behavior. Notably, this action is coupled to expression of chemokines that can expose the tumor to host immunity, potentially affecting response to therapy. Mechanistically, mutp53 fuels NF-κB activation while it dampens activation of ASK1/JNK by TNFα, and this action depends on mutp53 binding and inhibiting the tumor suppressor DAB2IP in the cytoplasm. Interfering with such interaction reduced aggressiveness of cancer cells in xenografts. This interaction is an unexplored mechanism by which mutant p53 can influence tumor evolution, with implications for our understanding of the complex role of inflammation in cancer.
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U2 - 10.1016/j.molcel.2014.10.013
DO - 10.1016/j.molcel.2014.10.013
M3 - Article
C2 - 25454946
AN - SCOPUS:84919480782
VL - 56
SP - 617
EP - 629
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -