Down-regulation of the Antisense Mitochondrial ncRNAs is a Unique Vulnerability of Cancer Cells and a Potential Target for Cancer Therapy

Authors:
Vidaurre S1, Fitzpatrick C2, Burzio VA3, Briones M2, Villota C2, Villegas J2, Echenique J2, Oliveira-Cruz L2, Araya M2, Borgna V2, Socías T2, Lopez C2, Avila R2, Burzio LO2
In:
Source: J Biol Chem
Publication Date: (2014)
Issue: M114: 558841
Research Area:
Basic Research
Cells used in publication:
Keratinocyte, (NHEK-Ad) human adult
Species: human
Tissue Origin: dermal
Keratinocyte, (NHEK-neo) human neonatal
Species: human
Tissue Origin: dermal
Abstract
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), which comprise 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 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 knock-down 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.