Abstract
TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV), most frequently identified in patients' biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67). In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / metabolism
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Antineoplastic Agents, Phytogenic / pharmacology*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Drug Carriers
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Gene Expression Regulation, Neoplastic*
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Genetic Therapy / methods
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Humans
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Male
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Mice
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Mice, SCID
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Nanoparticles / chemistry
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Oncogene Proteins, Fusion / antagonists & inhibitors*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms / therapy*
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RNA, Messenger / antagonists & inhibitors*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics*
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RNA, Small Interfering / metabolism
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Receptors, Adrenergic, alpha-2 / genetics
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Receptors, Adrenergic, alpha-2 / metabolism
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Signal Transduction
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Squalene / chemistry
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Squalene / metabolism
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Squalene / pharmacology*
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Treatment Outcome
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Tumor Burden
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Xenograft Model Antitumor Assays
Substances
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ADRA2A protein, human
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Antineoplastic Agents, Phytogenic
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Drug Carriers
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Oncogene Proteins, Fusion
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Adrenergic, alpha-2
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TMPRSS2-ERG fusion protein, human
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Squalene
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Caspase 3
Grants and funding
The research leading to these results has received funding from the Agence Nationale de Recherche (ANR), Program P2N, Grant N° NANO 00301.