Double Stranded-Rna-Mediated Activation of P21 Gene Induced Apoptosis and Cell Cycle Arrest in Renal Cell Carcinoma

Abstract

Small double stranded RNAs (dsRNA) are a new class of molecules which regulate gene expression. Accumulating data suggest that some dsRNA can function as tumor suppressors. Here we report further evidence on the potential of dsRNA mediated p21 induction. Using the human renal cell carcinoma cell line A498, we found that dsRNA targeting the p21 promoter significantly induced the expression of p21 mRNA and protein levels. As a result, dsP21 transfected cells had a significant decrease in cell viability with a concomitant G1 arrest. We also observed a significant increase in apoptosis. These findings were associated with a significant decrease in survivin mRNA and protein levels. This is the first report that demonstrates dsRNA mediated gene activation in renal cell carcinoma and suggests that forced over-expression of p21 may lead to an increase in apoptosis through a survivin dependent mechanism.

Small RNA-directed transcriptional control: New insights into mechanisms and therapeutic applications

“…Small RNA-mediated induction of the cyclin-dependent kinase inhibitor p21 led to inhibition of cell proliferation and survival in the T24 and J82 bladder cancer cell lines 80 and more recently in the A498 renal cancer cell line. 81 The effect on cell proliferation and survival was quite pronounced and persistent. Therefore, transcriptional activation of cell cycle inhibitors and tumour suppressor genes might be therapeutically beneficial for treatment of cancer, with effects comparable to the reintroduction of a tumour suppressor gene, like p53, by a gene replacement approach.…”

Antitumor Activity of Small Activating RNAs Induced PAWR Gene Activation in Human Bladder Cancer Cells

“…Their observation was supported by another group reporting similar findings [9] and subsequent studies suggests RNAa may be a general and conserved phenomenon of gene regulation [10][11][12][13][14][15][16][17]. Moreover, several studies demonstrate that restoration of p21 expression by saRNAs in different cancer cells has been shown to inhibit cell Ivyspring International Publisher proliferation and tumor growth [18][19][20][21][22][23]. Thus, RNAa holds great promise as an alternative to traditional vector-based systems and would supplement RNA-mediated gene silencing to broaden the gene pool susceptible to therapeutic regulation by small RNAs.…”

“…RNAa thus holds great promise as therapeutics for reactivation of functionally silenced or low expressed TSGs in cancer patients. Our group and others have obtained exciting results that up-regulation of p21 by saRNA could induce cell cycle arrest and apoptosis in human bladder cancer cells [18,19] and renal cell carcinoma cells [20] in vitro and inhibit the growth of xenograft prostate tumor [22] and orthotopic bladder tumor [23] in vivo.…”

Dual Role of TLR3 in Inflammation and Cancer Cell Apoptosis

“…Direct inhibition of tumor growth by TLR3 agonists has been reported in vitro for human breast, melanoma, prostate, head and neck, multiple myeloma, clear renal carcinoma, colon, lung, and cervical cancer cells [11,31,[42][43][44][45][46][47][48][49][50][51]. Two mechanisms contribute to the inhibition of tumor growth upon TLR3 activation; (i) decrease of proliferation and (ii) induction of apoptotic cell death.…”