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Down-regulation of the Antisense Mitochondrial Non-coding RNAs (ncRNAs) Is a Unique Vulnerability of Cancer Cells and a Potential Target for Cancer Therapy

S. Vidaurre,Christopher Fitzpatrick,V. Burzio,Macarena Briones,C. Villota,Jaime Villegas,Javiera Echenique,Luciana Oliveira-Cruz,Mariela Araya,Vincenzo Borgna,T. Socías,C. López,Rodolfo Ávila,L. Burzio

Published 2014 in Journal of Biological Chemistry

ABSTRACT

Background: Down-regulation of the antisense mitochondrial ncRNAs (ASncmtRNAs) is a general vulnerability of cancer cells. Results: Knocking down the ASncmtRNAs induces apoptosis, down-regulation of survivin, and generation of microRNAs. Conclusion: Induction of apoptosis in cancer cells is potentiated by down-regulation of survivin. Significance: The ASncmtRNAs represent a new potential therapeutic target for cancer. 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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