Journal of Biological Chemistry
Volume 289, Issue 39, September 2014, Pages 27182-27198
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Molecular Bases of Disease
Down-regulation of the Antisense Mitochondrial Non-coding RNAs (ncRNAs) Is a Unique Vulnerability of Cancer Cells and a Potential Target for Cancer Therapy*

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Hallmarks of cancer are fundamental principles involved in cancer progression. We propose an additional generalized hallmark of malignant transformation corresponding to the differential expression of a family of mitochondrial ncRNAs (ncmtRNAs) that comprises sense and antisense members, all of which contain stem-loop structures. Normal proliferating cells express sense (SncmtRNA) and antisense (ASncmtRNA) transcripts. In contrast, the ASncmtRNAs are down-regulated in tumor cells regardless of tissue of origin. Here we show that knockdown of the low copy number of the ASncmtRNAs in several tumor cell lines induces cell death by apoptosis without affecting the viability of normal cells. In addition, knockdown of ASncmtRNAs potentiates apoptotic cell death by inhibiting survivin expression, a member of the inhibitor of apoptosis (IAP) family. Down-regulation of survivin is at the translational level and is probably mediated by microRNAs generated by dicing of the double-stranded stem of the ASncmtRNAs, as suggested by evidence presented here, in which the ASncmtRNAs are bound to Dicer and knockdown of the ASncmtRNAs reduces reporter luciferase activity in a vector carrying the 3′-UTR of survivin mRNA. Taken together, down-regulation of the ASncmtRNAs constitutes a vulnerability or Achilles' heel of cancer cells, suggesting that the ASncmtRNAs are promising targets for cancer therapy.

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*

This work was supported by Comisión Nacional de Ciencia y Tecnología (Conicyt), Chile (Fondo Nacional de Ciencia y Tecnologia (Fondecyt) 1110835 and 1140345 (to V. A. B.), Fondecyt 11090060 (to C. V.), Fondecyt 1085210 (to J. V.), Fondef-D04I1338 (to J. V.), and CCTE-PFB16), and Universidad Andrés Bello, Chile (DI-34-09/R, DI-31-09/R, DI-28-09/R4, and DI-06-09/R).

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L. Lobos-González, V. Silva, S. Vidaurre, J. Echenique, M. Araya, M. Varas, L. Oliveira-Cruz, C. Fitzpatrick, F. Restovic, C. Villota, J. E. Villegas, C. López, T. Socías, L. O. Burzio, and V. A. Burzio, unpublished results.

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Both authors contributed equally to the work.

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The abbreviations used are:

    ncRNA

    non-coding RNA

    ncmtRNA

    non-coding mitochondrial RNA

    SncmtRNA

    sense ncmtRNA

    ASncmtRNA

    antisense ncmtRNA

    AS-1

    ASncmtRNA-1

    AS-2

    ASncmtRNA-2

    IAP

    inhibitor of apoptosis protein

    ASK

    ASncmtRNA knockdown

    ASO

    antisense oligodeoxynucleotide

    ASO-C

    control ASO

    miR

    microRNA

    PI

    propidium iodide

    PNA

    peptide nucleic acid

    PS

    phosphorothioate

    CCCP

    carbonyl cyanide 3-chlorophenylhydrazone

    ΔΨm

    mitochondrial membrane potential

    IP

    immunoprecipitate

    STP

    staurosporine

    Tb

    trypan blue

    EdU

    5-ethynyl-2′-deoxyuridine

    XIAP

    X-linked inhibitor of apoptosis protein

    HPV

    human papilloma virus

    HFK

    human foreskin keratinocyte

    HnEM

    human normal epidermal melanocyte

    HREC

    human normal renal epithelial cells

    HUVEC

    human umbilical vein endothelial cells

    RT

    room temperature

    FISH

    fluorescence in situ hybridization

    TEM

    transmission electron microscopy

    NT

    not treated

    z-VAD-fmk

    benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone.