PMID- 18421307
OWN - NLM
STAT- MEDLINE
DCOM- 20080903
LR  - 20131121
IS  - 1476-5500 (Electronic)
IS  - 0929-1903 (Linking)
VI  - 15
IP  - 7
DP  - 2008 Jul
TI  - Effects of lentivirus-mediated HIF-1alpha knockdown on hypoxia-related cisplatin 
      resistance and their dependence on p53 status in fibrosarcoma cells.
PG  - 449-55
LID - 10.1038/cgt.2008.4 [doi]
AB  - Therapy targeting hypoxia-inducible factor-1 (HIF-1) to reverse the 
      hypoxia-related drug resistance has received much interest. Despite a close 
      interaction between HIF-1 and p53 and that p53 mutation is seen in >50% of 
      tumors, whether HIF-1 silencing by targeted therapy depends on tumor p53 status 
      remains unknown. Two isogenic fibrosarcoma cells HT1080 (wild-type p53) and 
      HT1080-6TG (mutant p53) were transduced with HIF-1alpha-specific RNAi lentiviral 
      vectors and selected with blasticidin. Real-time PCR and western blot analysis of 
      HIF-1alpha mRNA and protein respectively validated the silencing effects. Cells 
      were first preconditioned under hypoxia (0.5% O(2)) for 4 h and then co-treated 
      with cisplatin for another 24 h. MTT was used for assessment of chemosensitivity 
      to cisplatin. Moreover, annexin V and propidium iodide staining was detected on 
      flow cytometry for analysis of cisplatin-induced apoptosis. Furthermore, changes 
      of some Bcl-2 family members were detected on western blotting. Exposure to 
      hypoxia significantly increased resistance to cisplatin than exposure to 
      normoxia. HIF-1alpha knockdown could reverse hypoxia-related resistance to 
      cisplatin and apoptotic resistance only in HT1080 cells, but had little effect on 
      HT1080-6TG cells. With HIF-1alpha knockdown, Bid expression was higher in HT1080 
      than in HT1080-6TG under hypoxia. In summary, HIF-1 targeted therapy to reverse 
      hypoxia-related cisplatin resistance depends on normal p53 status. Changes of Bid 
      expression levels under hypoxia might contribute in part to the differential 
      response to HIF-1alpha silencing in cells with different p53 status.
FAU - Hao, J
AU  - Hao J
AD  - Department of Oncology, Cancer Center, Qilu Hospital of Shandong University, 
      Jinan, China.
FAU - Song, X
AU  - Song X
FAU - Song, B
AU  - Song B
FAU - Liu, Y
AU  - Liu Y
FAU - Wei, L
AU  - Wei L
FAU - Wang, X
AU  - Wang X
FAU - Yu, J
AU  - Yu J
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080418
PL  - England
TA  - Cancer Gene Ther
JT  - Cancer gene therapy
JID - 9432230
RN  - 0 (Annexin A5)
RN  - 0 (DNA Primers)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Annexin A5/metabolism
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Hypoxia/*physiology
MH  - Cell Line, Tumor
MH  - Cisplatin/*pharmacology
MH  - DNA Primers/genetics
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance/*genetics
MH  - Flow Cytometry
MH  - Gene Silencing
MH  - Genetic Vectors/genetics
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/metabolism
MH  - Inhibitory Concentration 50
MH  - Lentivirus/*genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Suppressor Protein p53/*metabolism
EDAT- 2008/04/19 09:00
MHDA- 2008/09/04 09:00
CRDT- 2008/04/19 09:00
PHST- 2008/04/19 09:00 [pubmed]
PHST- 2008/09/04 09:00 [medline]
PHST- 2008/04/19 09:00 [entrez]
AID - cgt20084 [pii]
AID - 10.1038/cgt.2008.4 [doi]
PST - ppublish
SO  - Cancer Gene Ther. 2008 Jul;15(7):449-55. doi: 10.1038/cgt.2008.4. Epub 2008 Apr 
      18.