Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 8
Different ways to arrest proliferation of cancer cells by dsRNA
Elena L.Chernolovsksya, Tatyana O. Kabilova, Al`bina V. Vladimirova, Valentin V.
Vlassov
Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiav ave., 8,
Novosibirsk 630090, Russia, E-mail: elena_ch@niboch.nsc.ru
Deregulation of genes encoding components of signaling pathways are considered as a key
factor in the development of different types of tumors in humans. We investigated inhibition
of MYC genes by dsRNAs in KB-3-1, SC-N-MC and IMR-32 cells. Sequence-specific
siRNA (si3ex) targeted to the third exon of c-myc gene was found to decrease the level of cmyc,
but not N-myc mRNA. si3ex decreased the rate or even arrested the proliferation of cmyc
overexpressing cell lines KB-3-1 and SC-N-MC, but did not affect the proliferation of
IMR-32 (which overexpress N-myc). si2ex homological to the conservative region of the
second exon of both c- and N-myc was able to downregulate both genes and to reduce
proliferation of KB-3-1, SC-N-MC and IMR-32 cells. PKR or/and OAS1 mRNA levels were
not effected. Long double stranded RNAs and some short dsRNA can stimulate innate
cytokine responses in mammals, which can induce proliferation blockage, differentiation or
apoptosis in cancer cells. Long double stranded RNAs: dsMyc homologous to the 3 exon of cmyc
gene, dsGFP homologous to mRNA of EGFP gene and GU-rich siRNA (siI),
homologous to the intron sequence of human MDR1 gene were found to inhibit proliferation
and to decrease the mRNA level of interferon-sensitive genes: c-myc and beta-actin when
delivered into cancer human cells. The level of downregulation was march higher than that of
synthetic interferon inducer poly(I:C) and is likely depends on the properties of dsRNA: the
thermodynamic stability, nuclease resistance and affinity to dsRNA-binding proteins.
Antiproliferation activity of long dsRNA, displayed in the absence of transfection reagent,
was cell line specific and correlated with the ability of dsRNA to inhibit the expression of cmyc
and beta-actin genes. The elevation of PKR or/and OAS1 mRNA levels was detected in
all cells affected by long dsRNA and does not correlates with proliferation blockage. The data
suggest, that double stranded RNAs can serve as antiproliferative agents, acting sequencespecifically
or activating innate immunity response.
This work was supported by RFBR (grant No. 06-04-49480- ), RAS programs “Molecular
and Cellular Biology” and “Fundamental science for medicine”, Interdisciplinary grant from
SB RAS, FCSTP RI-012/001/254.
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