PMID- 19304334
OWN - NLM
STAT- MEDLINE
DCOM- 20090817
LR  - 20161125
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 50
IP  - 5
DP  - 2009 May
TI  - Selective ablation of Notch3 in HCC enhances doxorubicin's death promoting effect 
      by a p53 dependent mechanism.
PG  - 969-79
LID - 10.1016/j.jhep.2008.12.032 [doi]
AB  - BACKGROUND/AIMS: The functional roles of endogenous Notch3 and Notch1 for 
      protecting human hepatocellular carcinoma (HCC) lines against doxorubicin-induced 
      death have been investigated. We previously reported aberrant Notch3 and Notch4 
      up-regulation in HCC and we have extended these observations to include Notch1. 
      METHODS: Notch1 expression was assessed by immunohistochemistry and 
      immunoblotting. Notch3 and Notch1 expression were ablated in multiple HCC lines 
      by stable retroviral transduction of short hairpin RNAs (shRNAs). Effects on 
      doxorubicin sensitivity were evaluated with respect to cell growth, expression of 
      specific cell cycle effectors and multiple apoptotic parameters. RESULTS: Notch3 
      depletion increased p53 expression, doxorubicin uptake, DNA damage, the apoptosis 
      inducing effects of doxorubicin and also impeded the cell cycle progression of 
      HCC cells. Ablating p53 expression in Notch3 knockdown (KD) cells largely 
      abolished their enhanced doxorubicin sensitivity; and Notch3 KD in p53(-/-) Hep3B 
      cells failed to influence their response to doxorubicin. Although up-regulated in 
      most HCC, Notch1 (unlike Notch3) did not contribute to the doxorubicin resistance 
      of HCC lines. CONCLUSIONS: Our in vitro results represent the first evidence that 
      Notch3 silencing in combination with chemotherapeutics could conceivably provide 
      a novel strategy for HCC treatment that deserves further exploration.
FAU - Giovannini, Catia
AU  - Giovannini C
AD  - Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University 
      Hospital, Bologna, Italy. catia.giovannini@aosp.bo.it
FAU - Gramantieri, Laura
AU  - Gramantieri L
FAU - Chieco, Pasquale
AU  - Chieco P
FAU - Minguzzi, Manuela
AU  - Minguzzi M
FAU - Lago, Federica
AU  - Lago F
FAU - Pianetti, Simona
AU  - Pianetti S
FAU - Ramazzotti, Eric
AU  - Ramazzotti E
FAU - Marcu, Kenneth B
AU  - Marcu KB
FAU - Bolondi, Luigi
AU  - Bolondi L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090310
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (NOTCH3 protein, human)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Receptor, Notch3)
RN  - 0 (Receptors, Notch)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Antibiotics, Antineoplastic/pharmacology/*therapeutic use
MH  - Apoptosis/drug effects/*physiology
MH  - Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology
MH  - Cell Line, Tumor
MH  - DNA Damage/drug effects/physiology
MH  - Doxorubicin/pharmacology/*therapeutic use
MH  - Drug Resistance, Neoplasm/physiology
MH  - Female
MH  - Gene Deletion
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/metabolism/pathology
MH  - Male
MH  - Receptor, Notch1/genetics/metabolism
MH  - Receptor, Notch3
MH  - Receptors, Notch/genetics/*metabolism
MH  - Sensitivity and Specificity
MH  - Signal Transduction/physiology
MH  - Tumor Suppressor Protein p53/*metabolism
EDAT- 2009/03/24 09:00
MHDA- 2009/08/18 09:00
CRDT- 2009/03/24 09:00
PHST- 2008/07/03 00:00 [received]
PHST- 2008/11/05 00:00 [revised]
PHST- 2008/12/16 00:00 [accepted]
PHST- 2009/03/24 09:00 [entrez]
PHST- 2009/03/24 09:00 [pubmed]
PHST- 2009/08/18 09:00 [medline]
AID - S0168-8278(09)00064-6 [pii]
AID - 10.1016/j.jhep.2008.12.032 [doi]
PST - ppublish
SO  - J Hepatol. 2009 May;50(5):969-79. doi: 10.1016/j.jhep.2008.12.032. Epub 2009 Mar 
      10.