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 lungcancer 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. © 2011 Macmillan Publishers Limited. All rights reserved.