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Non-coding rRNA-mediated preferential killing in cancer cells is enhanced by suppression of autophagy in non-transformed counterpart.

ABSTRACT: Interest to anticancer agents targeting rRNA biogenesis is growing. Cis-non-coding rRNAs, alternative to primary rRNA, have been shown to regulate rRNA biogenesis. We have recently detected bidirectional non-coding rRNAs that carry ribozyme-like properties. Anti-antisense oligonucleotides complementary to antisense non-coding rRNAs markedly stabilized the bidirectional transcripts and induced cell death in mouse lung cells. Here, we demonstrated that the same oligonucleotide killed mouse lung-cancer cells preferentially, compared with non-cancer sister lines, suggesting its potential utility for cancer treatment. A human version of anti-antisense oligonucleotide, complementary to an rDNA intergenic site, mediated apoptosis primarily in cancer cells. Autophagic activation was largely undifferentiable between the anti-antisense and other oligonucleotides and accounted for the undesired cytotoxicity in non-cancer cells. Co-treatment with chloroquine, an autophagy inhibitor, reduced cytotoxicity in the non-cancer cells, but retained the anti-antisense-mediated killings in cancer cells. Furthermore, the anti-antisense oligonucleotide stabilized bidirectional non-coding rRNAs predominantly in human cancer cells and perturbed rRNA biogenesis. Contributions of non-coding rRNAs to cell death were proven by transfection of in -vitro-synthesized transcripts. Taken together, cancer/non-cancer cells respond differently to stabilization of non-coding rRNAs, and such differential responses provide a window of opportunity to enhance anticancer efficacy.

SUBMITTER: Hwang CJ

PROVIDER: S-EPMC3252735 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Non-coding rRNA-mediated preferential killing in cancer cells is enhanced by suppression of autophagy in non-transformed counterpart.

Hwang C J CJ Fields J R JR Shiao Y-H YH

Cell death & disease 20111208

Interest to anticancer agents targeting rRNA biogenesis is growing. Cis-non-coding rRNAs, alternative to primary rRNA, have been shown to regulate rRNA biogenesis. We have recently detected bidirectional non-coding rRNAs that carry ribozyme-like properties. Anti-antisense oligonucleotides complementary to antisense non-coding rRNAs markedly stabilized the bidirectional transcripts and induced cell death in mouse lung cells. Here, we demonstrated that the same oligonucleotide killed mouse lung-ca ...[more]

PMID: 22158478

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Project description:BackgroundPaclitaxel, a widely used chemotherapeutic drug, can induce apoptosis in variety of cancer cells. A previous study has shown preferential toxicity of paclitaxel to FLCN-deficient kidney cancer cell line, UOK257. In this report, we investigate the cellular and molecular mechanism of paclitaxel-induced autophagy and apoptosis in renal cancer cells with and without FLCN expression.MethodsTwo pairs of cell lines were used: FLCN siRNA-silenced ACHN cell line (ACHN-5968) and scrambled ACHN cell line (ACHN-sc); FLCN-null UOK257 cell line and UOK257-2 cell line restored with ectopic expression of FLCN. Autophagy was examined by western blot, GFP-LC3, transmission electron microscopy, and MDC assay. Cell viability and apoptosis were detected using MTT assay, DAPI stain and TUNEL assay. After inhibition of autophagy with 3-Methyladenine (3-MA) or Beclin 1 siRNA, cell viability and apoptosis were measured by MTT assay and TUNEL assay.ResultsAfter paclitaxel treatment, a dose-dependent decrease in cell viability and increase in apoptosis were observed in FLCN-deficient UOK257 and ACHN-5968 cells compared to their FLCN-expressing counterparts, suggesting that renal cancer cells without FLCN were more sensitive to paclitaxel. Enhanced autophagy was found to be associated with paclitaxel treatment in FLCN-deficient RCC cells. The MAPK pathway was also identified as a key pathway for the activation of autophagy in these kidney cancer cells. Inhibition of phosphorylated ERK with ERK inhibitor U0126 showed a significant decrease in autophagy. Furthermore, after inhibition of autophagy with 3-Methyladenine (3-MA) or Beclin 1 siRNA, apoptosis induced by paclitaxel was significantly increased in FLCN-deficient UOK257 and ACHN-5968 cells.ConclusionsPreferential toxicity of paclitaxel to FLCN-deficient kidney cancer cells is associated with enhanced autophagy. Suppression of autophagy further enhances paclitaxel-induced apoptosis in FLCN-deficient renal cancer cells. Our results suggest that paclitaxel combined with an autophagy inhibitor might be a potentially more effective chemotherapeutic approach for FLCN-deficient renal cancer.

Dataset Information

Non-coding rRNA-mediated preferential killing in cancer cells is enhanced by suppression of autophagy in non-transformed counterpart.

Publications

Non-coding rRNA-mediated preferential killing in cancer cells is enhanced by suppression of autophagy in non-transformed counterpart.

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