Reactivating p53 functions by suppressing its novel inhibitor iASPP: a potential therapeutic opportunity in p53 wild-type tumors.
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.
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Peixin
P
Dong
Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Kei
K
Ihira
Department of Stem Cell Biology, Hokkaido University Graduate School of Medicine, Kita-Ku, Sapporo, Japan.
Junichi
J
Hamada
Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Hidemichi
H
Watari
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Takahiro
T
Yamada
Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Masayoshi
M
Hosaka
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Sharon J B
SJ
Hanley
Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Masataka
M
Kudo
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.|Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
Noriaki
N
Sakuragi
D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D009369:Neoplasms / Q000503:physiopathology*; D012097:Repressor Proteins / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53
iASPP; invasion; microRNA; reactivation of p53; review