TY - JOUR
T1 - A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53
AU - Zhang, Qi
AU - Zeng, Shelya X.
AU - Zhang, Yu
AU - Zhang, Yiwei
AU - Ding, Derong
AU - Ye, Qizhuang
AU - Meroueh, Samy O.
AU - Lu, Hua
PY - 2012/4
Y1 - 2012/4
N2 - Although ∼50% of all types of human cancers harbour wild-type TP53, this p53 tumour suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX or SIRT1. Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, INZ inhibits cell proliferation, induces senescence and tumour-specific apoptosis, and represses the growth of xenograft tumours derived from p53-harbouring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumour-bearing SCID mice. Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.
AB - Although ∼50% of all types of human cancers harbour wild-type TP53, this p53 tumour suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX or SIRT1. Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, INZ inhibits cell proliferation, induces senescence and tumour-specific apoptosis, and represses the growth of xenograft tumours derived from p53-harbouring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumour-bearing SCID mice. Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.
KW - Apoptosis
KW - Inauhzin
KW - P53
KW - SIRT1
KW - Small molecule inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84859381463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859381463&partnerID=8YFLogxK
U2 - 10.1002/emmm.201100211
DO - 10.1002/emmm.201100211
M3 - Article
C2 - 22331558
AN - SCOPUS:84859381463
SN - 1757-4676
VL - 4
SP - 298
EP - 312
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
ER -