Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors

Christopher Fitzpatrick, Maximiliano F. Bendek, Macarena Briones, Nicole Farfán, Valeria A. Silva, Gino Nardocci, Martín Montecino, Anne Boland, Jean François Deleuze, Jaime Villegas, Claudio Villota, Verónica Silva, Lorena Lobos-Gonzalez, Vincenzo Borgna, Eric Barrey, Luis O. Burzio, Verónica A. Burzio

Resultado de la investigación: Article

Resumen

The family of long noncoding mitochondrial RNAs (ncmtRNAs), comprising sense (SncmtRNA), and antisense (ASncmtRNA-1 and ASncmtRNA-2) members, are differentially expressed according to cell proliferative status; SncmtRNA is expressed in all proliferating cells, while ASncmtRNAs are expressed in normal proliferating cells, but is downregulated in tumor cells. ASncmtRNA knockdown with an antisense oligonucleotide induces massive apoptosis in tumor cell lines, without affecting healthy cells. Apoptotic death is preceded by proliferation blockage, suggesting that these transcripts are involved in cell cycle regulation. Here, we show that ASncmtRNA knockdown induces cell death preceded by proliferative blockage in three different human breast cancer cell lines. This effect is mediated by downregulation of the key cell cycle progression factors cyclin B1, cyclin D1, CDK1, CDK4, and survivin, the latter also constituting an essential inhibitor of apoptosis, underlying additionally the onset of apoptosis. The treatment also induces an increase in the microRNA hsa-miR-4485-3p, whose sequence maps to ASncmtRNA-2 and transfection of MDA-MB-231 cells with a mimic of this miRNA induces cyclin B1 and D1 downregulation. Other miRNAs that are upregulated include nuclear-encoded hsa-miR-5096 and hsa-miR-3609, whose mimics downregulate CDK1. Our results suggest that ASncmtRNA targeting blocks tumor cell proliferation through reduction of essential cell cycle proteins, mediated by mitochondrial and nuclear miRNAs. This work adds to the elucidation of the molecular mechanisms behind cell cycle arrest preceding tumor cell apoptosis induced by ASncmtRNA knockdown. As proof-of-concept, we show that in vivo knockdown of ASncmtRNAs results in drastic inhibition of tumor growth in a xenograft model of MDA-MB-231 subcutaneous tumors, further supporting this approach for the development of new therapeutic strategies against breast cancer.

Idioma originalEnglish
Número de artículo423
PublicaciónCell Death and Disease
Volumen10
N.º6
DOI
EstadoPublished - 1 jun 2019

Huella dactilar

Cell Cycle Checkpoints
Cell Cycle
Breast Neoplasms
MicroRNAs
Growth
Down-Regulation
Neoplasms
Apoptosis
Cyclin B1
Cyclin D1
Long Noncoding RNA
Cell Cycle Proteins
Antisense Oligonucleotides
Tumor Cell Line
Heterografts
Transfection
Cell Death
Cell Proliferation
Cell Line

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Citar esto

Fitzpatrick, Christopher ; Bendek, Maximiliano F. ; Briones, Macarena ; Farfán, Nicole ; Silva, Valeria A. ; Nardocci, Gino ; Montecino, Martín ; Boland, Anne ; Deleuze, Jean François ; Villegas, Jaime ; Villota, Claudio ; Silva, Verónica ; Lobos-Gonzalez, Lorena ; Borgna, Vincenzo ; Barrey, Eric ; Burzio, Luis O. ; Burzio, Verónica A. / Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors. En: Cell Death and Disease. 2019 ; Vol. 10, N.º 6.
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title = "Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors",
abstract = "The family of long noncoding mitochondrial RNAs (ncmtRNAs), comprising sense (SncmtRNA), and antisense (ASncmtRNA-1 and ASncmtRNA-2) members, are differentially expressed according to cell proliferative status; SncmtRNA is expressed in all proliferating cells, while ASncmtRNAs are expressed in normal proliferating cells, but is downregulated in tumor cells. ASncmtRNA knockdown with an antisense oligonucleotide induces massive apoptosis in tumor cell lines, without affecting healthy cells. Apoptotic death is preceded by proliferation blockage, suggesting that these transcripts are involved in cell cycle regulation. Here, we show that ASncmtRNA knockdown induces cell death preceded by proliferative blockage in three different human breast cancer cell lines. This effect is mediated by downregulation of the key cell cycle progression factors cyclin B1, cyclin D1, CDK1, CDK4, and survivin, the latter also constituting an essential inhibitor of apoptosis, underlying additionally the onset of apoptosis. The treatment also induces an increase in the microRNA hsa-miR-4485-3p, whose sequence maps to ASncmtRNA-2 and transfection of MDA-MB-231 cells with a mimic of this miRNA induces cyclin B1 and D1 downregulation. Other miRNAs that are upregulated include nuclear-encoded hsa-miR-5096 and hsa-miR-3609, whose mimics downregulate CDK1. Our results suggest that ASncmtRNA targeting blocks tumor cell proliferation through reduction of essential cell cycle proteins, mediated by mitochondrial and nuclear miRNAs. This work adds to the elucidation of the molecular mechanisms behind cell cycle arrest preceding tumor cell apoptosis induced by ASncmtRNA knockdown. As proof-of-concept, we show that in vivo knockdown of ASncmtRNAs results in drastic inhibition of tumor growth in a xenograft model of MDA-MB-231 subcutaneous tumors, further supporting this approach for the development of new therapeutic strategies against breast cancer.",
author = "Christopher Fitzpatrick and Bendek, {Maximiliano F.} and Macarena Briones and Nicole Farf{\'a}n and Silva, {Valeria A.} and Gino Nardocci and Mart{\'i}n Montecino and Anne Boland and Deleuze, {Jean Fran{\cc}ois} and Jaime Villegas and Claudio Villota and Ver{\'o}nica Silva and Lorena Lobos-Gonzalez and Vincenzo Borgna and Eric Barrey and Burzio, {Luis O.} and Burzio, {Ver{\'o}nica A.}",
year = "2019",
month = "6",
day = "1",
doi = "10.1038/s41419-019-1649-3",
language = "English",
volume = "10",
journal = "Cell Death and Disease",
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Fitzpatrick, C, Bendek, MF, Briones, M, Farfán, N, Silva, VA, Nardocci, G, Montecino, M, Boland, A, Deleuze, JF, Villegas, J, Villota, C, Silva, V, Lobos-Gonzalez, L, Borgna, V, Barrey, E, Burzio, LO & Burzio, VA 2019, 'Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors', Cell Death and Disease, vol. 10, n.º 6, 423. https://doi.org/10.1038/s41419-019-1649-3

Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors. / Fitzpatrick, Christopher; Bendek, Maximiliano F.; Briones, Macarena; Farfán, Nicole; Silva, Valeria A.; Nardocci, Gino; Montecino, Martín; Boland, Anne; Deleuze, Jean François; Villegas, Jaime; Villota, Claudio; Silva, Verónica; Lobos-Gonzalez, Lorena; Borgna, Vincenzo; Barrey, Eric; Burzio, Luis O.; Burzio, Verónica A.

En: Cell Death and Disease, Vol. 10, N.º 6, 423, 01.06.2019.

Resultado de la investigación: Article

TY - JOUR

T1 - Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors

AU - Fitzpatrick, Christopher

AU - Bendek, Maximiliano F.

AU - Briones, Macarena

AU - Farfán, Nicole

AU - Silva, Valeria A.

AU - Nardocci, Gino

AU - Montecino, Martín

AU - Boland, Anne

AU - Deleuze, Jean François

AU - Villegas, Jaime

AU - Villota, Claudio

AU - Silva, Verónica

AU - Lobos-Gonzalez, Lorena

AU - Borgna, Vincenzo

AU - Barrey, Eric

AU - Burzio, Luis O.

AU - Burzio, Verónica A.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - The family of long noncoding mitochondrial RNAs (ncmtRNAs), comprising sense (SncmtRNA), and antisense (ASncmtRNA-1 and ASncmtRNA-2) members, are differentially expressed according to cell proliferative status; SncmtRNA is expressed in all proliferating cells, while ASncmtRNAs are expressed in normal proliferating cells, but is downregulated in tumor cells. ASncmtRNA knockdown with an antisense oligonucleotide induces massive apoptosis in tumor cell lines, without affecting healthy cells. Apoptotic death is preceded by proliferation blockage, suggesting that these transcripts are involved in cell cycle regulation. Here, we show that ASncmtRNA knockdown induces cell death preceded by proliferative blockage in three different human breast cancer cell lines. This effect is mediated by downregulation of the key cell cycle progression factors cyclin B1, cyclin D1, CDK1, CDK4, and survivin, the latter also constituting an essential inhibitor of apoptosis, underlying additionally the onset of apoptosis. The treatment also induces an increase in the microRNA hsa-miR-4485-3p, whose sequence maps to ASncmtRNA-2 and transfection of MDA-MB-231 cells with a mimic of this miRNA induces cyclin B1 and D1 downregulation. Other miRNAs that are upregulated include nuclear-encoded hsa-miR-5096 and hsa-miR-3609, whose mimics downregulate CDK1. Our results suggest that ASncmtRNA targeting blocks tumor cell proliferation through reduction of essential cell cycle proteins, mediated by mitochondrial and nuclear miRNAs. This work adds to the elucidation of the molecular mechanisms behind cell cycle arrest preceding tumor cell apoptosis induced by ASncmtRNA knockdown. As proof-of-concept, we show that in vivo knockdown of ASncmtRNAs results in drastic inhibition of tumor growth in a xenograft model of MDA-MB-231 subcutaneous tumors, further supporting this approach for the development of new therapeutic strategies against breast cancer.

AB - The family of long noncoding mitochondrial RNAs (ncmtRNAs), comprising sense (SncmtRNA), and antisense (ASncmtRNA-1 and ASncmtRNA-2) members, are differentially expressed according to cell proliferative status; SncmtRNA is expressed in all proliferating cells, while ASncmtRNAs are expressed in normal proliferating cells, but is downregulated in tumor cells. ASncmtRNA knockdown with an antisense oligonucleotide induces massive apoptosis in tumor cell lines, without affecting healthy cells. Apoptotic death is preceded by proliferation blockage, suggesting that these transcripts are involved in cell cycle regulation. Here, we show that ASncmtRNA knockdown induces cell death preceded by proliferative blockage in three different human breast cancer cell lines. This effect is mediated by downregulation of the key cell cycle progression factors cyclin B1, cyclin D1, CDK1, CDK4, and survivin, the latter also constituting an essential inhibitor of apoptosis, underlying additionally the onset of apoptosis. The treatment also induces an increase in the microRNA hsa-miR-4485-3p, whose sequence maps to ASncmtRNA-2 and transfection of MDA-MB-231 cells with a mimic of this miRNA induces cyclin B1 and D1 downregulation. Other miRNAs that are upregulated include nuclear-encoded hsa-miR-5096 and hsa-miR-3609, whose mimics downregulate CDK1. Our results suggest that ASncmtRNA targeting blocks tumor cell proliferation through reduction of essential cell cycle proteins, mediated by mitochondrial and nuclear miRNAs. This work adds to the elucidation of the molecular mechanisms behind cell cycle arrest preceding tumor cell apoptosis induced by ASncmtRNA knockdown. As proof-of-concept, we show that in vivo knockdown of ASncmtRNAs results in drastic inhibition of tumor growth in a xenograft model of MDA-MB-231 subcutaneous tumors, further supporting this approach for the development of new therapeutic strategies against breast cancer.

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U2 - 10.1038/s41419-019-1649-3

DO - 10.1038/s41419-019-1649-3

M3 - Article

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AN - SCOPUS:85067064253

VL - 10

JO - Cell Death and Disease

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