title: Down-regulation of the antisense mitochondrial non-coding RNAs (ncRNAs) is a unique vulnerability of cancer cells and a potential target for cancer therapy.
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) 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.
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Departamento de Ciencias Químicas y Biológicas, Universidad Bernardo ÓHiggins, General Gana 1702, Santiago, Chile.
authors.forename: Soledad
authors.initials: S
authors.lastname: Vidaurre
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Fundación Ciencia para la Vida, Zañartu 1482, Ñuñoa, Santiago 7780272, Chile,; Facultad de Ciencias Biológicas and Universidad Andrés Bello, República 252, Santiago 8370134, Chile.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fitzpatrick
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Fundación Ciencia para la Vida, Zañartu 1482, Ñuñoa, Santiago 7780272, Chile,; Facultad de Ciencias Biológicas and Universidad Andrés Bello, República 252, Santiago 8370134, Chile. Electronic address: vburzio@gmail.com.
authors.forename: Verónica A
authors.initials: VA
authors.lastname: Burzio
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Facultad de Ciencias Biológicas and Universidad Andrés Bello, República 252, Santiago 8370134, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Briones
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Fundación Ciencia para la Vida, Zañartu 1482, Ñuñoa, Santiago 7780272, Chile,; Facultad de Ciencias Biológicas and Universidad Andrés Bello, República 252, Santiago 8370134, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Villota
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Fundación Ciencia para la Vida, Zañartu 1482, Ñuñoa, Santiago 7780272, Chile,; Facultad de Ciencias Biológicas and Universidad Andrés Bello, República 252, Santiago 8370134, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Villegas
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Javiera
authors.initials: J
authors.lastname: Echenique
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Fundación Ciencia para la Vida, Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Luciana
authors.initials: L
authors.lastname: Oliveira-Cruz
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Mariela
authors.initials: M
authors.lastname: Araya
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Facultad de Medicina, Universidad Andrés Bello, República 252, Santiago 8370134, Chile, and.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Borgna
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Teresa
authors.initials: T
authors.lastname: Socías
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Constanza
authors.initials: C
authors.lastname: Lopez
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Avila
authors.affiliation: Andes Biotechnologies SA and Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Fundación Ciencia para la Vida, Zañartu 1482, Ñuñoa, Santiago 7780272, Chile,; Facultad de Ciencias Biológicas and Universidad Andrés Bello, República 252, Santiago 8370134, Chile. Electronic address: lburzio@gmail.com.
authors.forename: Luis O
authors.initials: LO
authors.lastname: Burzio
mesh_terms: D017209:Apoptosis / Q000235:genetics; D018938:Caco-2 Cells; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics; D016372:RNA, Antisense / Q000096:biosynthesis* / Q000235:genetics; D000077278:RNA, Mitochondrial; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D022661:RNA, Untranslated / Q000096:biosynthesis* / Q000235:genetics; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D016372:RNA, Antisense; D000077278:RNA, Mitochondrial; D012334:RNA, Neoplasm; D022661:RNA, Untranslated; D000077022:Survivin; D012313:RNA
keywords: Apoptosis; Cancer; MicroRNA (miRNA); Mitochondria; Survivin; ncRNA
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