title: 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.
authors.affiliation: Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Hwang
authors.forename: J R
authors.initials: JR
authors.lastname: Fields
authors.forename: Y-H
authors.initials: YH
authors.lastname: Shiao
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009841:Oligonucleotides / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000633:toxicity; D012335:RNA, Ribosomal / Q000378:metabolism*; D022661:RNA, Untranslated / Q000378:metabolism*
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012335:RNA, Ribosomal; D022661:RNA, Untranslated; C477371:locked nucleic acid; D002738:Chloroquine