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Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression

The development of cancer-specific therapeutics has been limited because most healthy cells and cancer cells depend on common pathways. Pyruvate kinase (PK) exists in M1 (PKM1) and M2 (PKM2) isoforms. PKM2, whose expression in cancer cells results in aerobic glycolysis and is suggested to bestow a s...

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Detalles Bibliográficos
Autores principales: Goldberg, Michael S., Sharp, Phillip A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280873/
https://www.ncbi.nlm.nih.gov/pubmed/22271574
http://dx.doi.org/10.1084/jem.20111487
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author Goldberg, Michael S.
Sharp, Phillip A.
author_facet Goldberg, Michael S.
Sharp, Phillip A.
author_sort Goldberg, Michael S.
collection PubMed
description The development of cancer-specific therapeutics has been limited because most healthy cells and cancer cells depend on common pathways. Pyruvate kinase (PK) exists in M1 (PKM1) and M2 (PKM2) isoforms. PKM2, whose expression in cancer cells results in aerobic glycolysis and is suggested to bestow a selective growth advantage, is a promising target. Because many oncogenes impart a common alteration in cell metabolism, inhibition of the M2 isoform might be of broad applicability. We show that several small interfering (si) RNAs designed to target mismatches between the M2 and M1 isoforms confer specific knockdown of the former, resulting in decreased viability and increased apoptosis in multiple cancer cell lines but less so in normal fibroblasts or endothelial cells. In vivo delivery of siPKM2 additionally causes substantial tumor regression of established xenografts. Our results suggest that the inherent nucleotide-level specificity of siRNA can be harnessed to develop therapeutics that target isoform-specific exons in genes exhibiting differential splicing patterns in various cell types.
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spelling pubmed-32808732012-08-13 Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression Goldberg, Michael S. Sharp, Phillip A. J Exp Med Brief Definitive Report The development of cancer-specific therapeutics has been limited because most healthy cells and cancer cells depend on common pathways. Pyruvate kinase (PK) exists in M1 (PKM1) and M2 (PKM2) isoforms. PKM2, whose expression in cancer cells results in aerobic glycolysis and is suggested to bestow a selective growth advantage, is a promising target. Because many oncogenes impart a common alteration in cell metabolism, inhibition of the M2 isoform might be of broad applicability. We show that several small interfering (si) RNAs designed to target mismatches between the M2 and M1 isoforms confer specific knockdown of the former, resulting in decreased viability and increased apoptosis in multiple cancer cell lines but less so in normal fibroblasts or endothelial cells. In vivo delivery of siPKM2 additionally causes substantial tumor regression of established xenografts. Our results suggest that the inherent nucleotide-level specificity of siRNA can be harnessed to develop therapeutics that target isoform-specific exons in genes exhibiting differential splicing patterns in various cell types. The Rockefeller University Press 2012-02-13 /pmc/articles/PMC3280873/ /pubmed/22271574 http://dx.doi.org/10.1084/jem.20111487 Text en © 2012 Goldberg and Sharp This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Goldberg, Michael S.
Sharp, Phillip A.
Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression
title Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression
title_full Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression
title_fullStr Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression
title_full_unstemmed Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression
title_short Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression
title_sort pyruvate kinase m2-specific sirna induces apoptosis and tumor regression
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280873/
https://www.ncbi.nlm.nih.gov/pubmed/22271574
http://dx.doi.org/10.1084/jem.20111487
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