HSF1 overexpression enhances oncolytic effect of replicative adenovirus.
BACKGROUND
E1B55kD deleted oncolytic adenovirus was designed to achieve cancer-specific cytotoxicity, but showed limitations in clinical study. To find a method to increase its efficacy, we investigated the correlation between oncolytic effect of such oncolytic adenovirus Adel55 and intracellular heat shock transcription factor 1 (HSF1) activity.


METHODS
In the present study, human breast cancer cell line Bcap37 was stably transfected with constitutively active HSF1 (cHSF1) or HSF1 specific siRNA (HSF1i) to establish increased or decreased HSF1 expression levels. Cytotoxicity of Adel55 was analyzed in these cell lines in vitro and in vivo. Furthermore, Adel55 incorporated with cHSF1 (Adel55-cHSF1) was used to treat various tumor xenografts.


RESULTS
Adel55 could achieve more efficient oncolysis in cHSF1 transfected Bcap37 cells, both in vitro and in vivo. However, inhibition of HSF1 expression by HSF1i could rescue Bcap37 cell line from oncolysis by Adel55. A time course study of viral replication established a correlation between higher replication of Adel55 and cytolysis or tumor growth inhibition. Then, we constructed Adel55-cHSF1 for tumor gene therapy and demonstrated that it is more potent than Adel55 itself in oncolysis and replication in both Bcap37 and SW620 xenografts.


CONCLUSIONS
cHSF1 enhances the Adel55 cell-killing potential through increasing the viral replication and is a potential therapeutic implication to augment the potential of E1B55kD deleted oncolytic adenovirus by increasing its burst.
Wang
Cheng
C
Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China.
Dai
Zhehao
Z
Fan
Rong
R
Deng
Youwen
Y
Lv
Guohua
G
Lu
Guangxiu
G
D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D000076249:Heat Shock Transcription Factors; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D000091402:Prohibitins; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D014157:Transcription Factors
Mol Cell Biol. 1983 Nov;3(11):2058-65
6689197
Biochem Biophys Res Commun. 2002 Feb 8;290(5):1454-61
11820785
Curr Cancer Drug Targets. 2007 Mar;7(2):133-9
17346104
Nat Med. 2000 Aug;6(8):879-85
10932224
Annu Rev Genet. 1988;22:631-77
2853609
Cancer Cell. 2005 Jul;8(1):61-74
16023599
J Gen Virol. 1998 Sep;79 ( Pt 9):2239-47
9747734
Biochem Biophys Res Commun. 2004 Aug 27;321(3):736-45
15358168
J Biol Chem. 1992 Nov 5;267(31):21987-90
1429548
Cell. 1994 Dec 30;79(7):1129-32
8001149
Nat Med. 1997 Jun;3(6):639-45
9176490
Cancer Res. 2001 Dec 1;61(23):8361-5
11731408
Mol Cell Biol. 1985 Feb;5(2):330-41
2858050
Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10345-9
1438220
Cancer Res. 2001 Oct 15;61(20):7464-72
11606381
Cell. 1982 Jul;29(3):913-9
7151177
Oncogene. 1999 Sep 9;18(36):5032-43
10490840
J Gen Virol. 1977 Jul;36(1):59-74
886304
Mol Cell Biol. 1983 Jul;3(7):1212-21
6688459
Cancer Res. 2000 Nov 15;60(22):6359-66
11103798
Nature. 2000 Sep 14;407(6801):207-11
11001061
Cancer Gene Ther. 2007 Nov;14(11):885-93
17704755