Alterations of the gene expression profile in renal cell carcinoma after treatment with the histone deacetylase-inhibitor valproic acid and interferon-alpha.
OBJECTIVE
Renal cell carcinoma (RCC) is highly resistant to chemotherapy and unresponsive to radio- and immunotherapy. Recently, we have documented that the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) in combination with low-dosed interferon (IFN)-alpha significantly inhibits RCC proliferation and adhesion in vitro and in vivo. The current study investigated the effects of these compounds on gene transcription of metastatic RCC cell line Caki-1 after 3 and 5 days exposure.


METHODS
To evaluate the gene expression profiles of the RCC cells, we performed microarray analysis using Affymetrix GeneChip. Selected significant genes were further validated by Real Time PCR.


RESULTS
Microarray revealed that VPA altered genes that are involved in cell growth, cell survival, immune response, cell motility and cell adhesion. Combination of VPA with IFN-alpha not only enhanced the effects on gene transcription but also resulted in the expression of novel genes, which were not induced by either VPA or IFN-alpha alone. Among the up-regulated genes were chemokines (CXCL10, CXCL11, CXCL16) and integrins (ITGA2, ITGA4, ITGA5, ITGA6, ITGA7). Genes encoding for adhesion molecules (NCAM1, ICAM1, VCAM1) were also modulated. Real Time PCR approved these findings.


CONCLUSIONS
This data provides insight into the molecular mechanism of action of the combined treatment of VPA and IFN-alpha in RCC. Implications are that the combined application of VPA and IFN-alpha may represent a more efficient alternative to existing therapy options for RCC.
Juengel
E
E
Klinik für Urologie und Kinderurologie, Zentrum der Chirurgie, Klinikum der Johann Wolfgang Goethe-Universität, Interdisziplinäres Forschungs- und Laborgebäude, Chirurgische Forschung, Haus 25, Zi 212, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. juengel@med.uni-frankfurt.de
Bhasin
M
M
Libermann
T
T
Barth
S
S
Michaelis
M
M
Cinatl
J
J
Jones
J
J
Hudak
L
L
Jonas
D
D
Blaheta
R A
RA
D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D046228:Microarray Analysis; D014635:Valproic Acid / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D007155:Immunologic Factors; D016898:Interferon-alpha; D014635:Valproic Acid