TY - JOUR
T1 - Mutant p53 potentiates the oncogenic effects of insulin by inhibiting the tumor suppressor DAB2IP
AU - Valentino, Elena
AU - Bellazzo, Arianna
AU - Di Minin, Giulio
AU - Sicari, Daria
AU - Apollonio, Mattia
AU - Scognamiglio, Giosuè
AU - Di Bonito, Maurizio
AU - Botti, Gerardo
AU - Del Sal, Giannino
AU - Collavin, Licio
PY - 2017/7/18
Y1 - 2017/7/18
N2 - Obesity and type 2 diabetes are significant risk factors for malignancies, being associated with chronic inflammation and hyperinsulinemia. In this context, insulin can synergize with inflammation to promote proliferation, survival, and dissemination of cancer cells. Point mutation of p53 is a frequent event and a significant factor in cancer development and progression. Mutant p53 protein(s) (mutp53) can acquire oncogenic properties that increase metastasis, proliferation, and cell survival. We report that breast and prostate cancer cells with mutant p53 respond to insulin stimulation by increasing cell proliferation and invasivity, and that such a response depends on the presence of mutp53. Mechanistically, we find that mutp53 augments insulin-induced AKT1 activation by binding and inhibiting the tumor suppressor DAB2IP (DAB2-interacting protein) in the cytoplasm. This molecular axis reveals a specific gain of function for mutant p53 in the response to insulin stimulation, offering an additional perspective to understand the relationship between hyperinsulinemia and cancer evolution.
AB - Obesity and type 2 diabetes are significant risk factors for malignancies, being associated with chronic inflammation and hyperinsulinemia. In this context, insulin can synergize with inflammation to promote proliferation, survival, and dissemination of cancer cells. Point mutation of p53 is a frequent event and a significant factor in cancer development and progression. Mutant p53 protein(s) (mutp53) can acquire oncogenic properties that increase metastasis, proliferation, and cell survival. We report that breast and prostate cancer cells with mutant p53 respond to insulin stimulation by increasing cell proliferation and invasivity, and that such a response depends on the presence of mutp53. Mechanistically, we find that mutp53 augments insulin-induced AKT1 activation by binding and inhibiting the tumor suppressor DAB2IP (DAB2-interacting protein) in the cytoplasm. This molecular axis reveals a specific gain of function for mutant p53 in the response to insulin stimulation, offering an additional perspective to understand the relationship between hyperinsulinemia and cancer evolution.
KW - AIP1
KW - AKT
KW - Hyperinsulinemia
KW - Mutant p53
KW - Obesity
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U2 - 10.1073/pnas.1700996114
DO - 10.1073/pnas.1700996114
M3 - Article
AN - SCOPUS:85024397384
VL - 114
SP - 7623
EP - 7628
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 29
ER -