Reactivating p53 functions by suppressing its novel inhibitor iASPP: a potential therapeutic opportunity in p53 wild-type tumors
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Peixin Dong1, Kei Ihira2, Junichi Hamada3, Hidemichi Watari2, Takahiro Yamada1, Masayoshi Hosaka2, Sharon J.B. Hanley1, Masataka Kudo2 and Noriaki Sakuragi1,2
1 Department of Women’s Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
2 Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
3 Department of Stem Cell Biology, Hokkaido University Graduate School of Medicine, Kita-Ku, Sapporo, Japan
Peixin Dong, email:
Keywords: review, reactivation of p53, iASPP, microRNA, invasion
Received: May 04, 2015 Accepted: June 28, 2015 Published: July 13, 2015
Although mutational inactivation of p53 is found in 50% of all human tumors, a subset of tumors display defective p53 function, but retain wild-type (WT) p53. Here, direct and indirect mechanisms leading to the loss of WT p53 activities are discussed. We summarize the oncogenic roles of iASPP, an inhibitor of WT p53, in promoting proliferation, invasion, drug or radiation-resistance and metastasis. From the therapeutic view, we highlight promising perspectives of microRNA-124, peptide and small molecules that reduce or block iASPP for the treatment of cancer. High iASPP expression enhances proliferation, aggressive behavior, the resistance to radiation/chemotherapy and correlates with poor prognosis in a range of human tumors. Overexpression of iASPP accelerates tumorigenesis and invasion through p53-dependent and p53-independent mechanisms. MicroRNA-124 directly targets iASPP and represses the growth and invasiveness of cancer cells. The disruption of iASPP-p53 interaction by a p53-derived peptide A34 restores p53 function in cancer cells. The inhibition of iASPP phosphorylation with small molecules induces p53-dependent apoptosis and growth suppression. The mechanisms underlying aberrant expression of iASPP in human tumors should be further investigated. Reactivating WT p53 functions by targeting its novel inhibitor iASPP holds promise for potential therapeutic interventions in the treatment of WT p53-containing tumors.
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