Itch inhibition regulates chemosensitivity in vitro.
Itch is a member of the HECT family of ubiquitin E3 ligases, and regulates the stability of several proteins involved in response to genotoxic stress. We have previously shown that p73 and p63, two members of the p53 family of tumour suppressors, are targets for Itch-mediated ubiquitylation and degradation. Here, we show that depletion of Itch by RNA interference augments apoptosis upon treatment with chemotherapeutic drugs. We also show that cells with no functional p53 are more sensitive to Itch depletion, highlighting the importance that changes in levels of Itch may play in majority of cancers, where p53 is absent or mutated. Furthermore, reintroduction of Itch in fibroblasts obtained from Itch deficient mice results in reduced cell death upon DNA damage. Overall our findings suggest that inhibition of Itch potentiates the effect of chemotherapeutic drugs revealing the pharmacological potentials of targeting Itch for cancer therapy.
Hansen
T M
TM
Medical Research Council, Toxicology Unit, Hodgkin Building, P.O. Box 138, Leicester University, Lancaster Road, Leicester LE1 9HN, UK.
Rossi
M
M
Roperch
J P
JP
Ansell
K
K
Simpson
K
K
Taylor
D
D
Mathon
N
N
Knight
R A
RA
Melino
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D012097:Repressor Proteins; C432966:ITCH protein, human; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases