Hsp70 silencing with siRNA in nanocarriers enhances cancer cell death induced by the inhibitor of Hsp90

Matokanović, Mirela; Barišić, Karmela; Filipović-Grčić, Jelena; Maysinger, Dušica

doi:10.1016/j.ejps.2013.04.001

Cited by 42 publications

(24 citation statements)

References 58 publications

(62 reference statements)

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“…Indeed, the targeting of stress response proteins has remarkable potential for the development of molecular treatments. Simultaneous inhibition of expression of both HOP ligands Hsp70 and Hsp90 reduced proliferation and promoted apoptosis in GBM cell lines in vitro [50]. Furthermore, HOP performs an important function in compensatory mechanisms of stress responses in tumor cells [51], further supporting its relevance in GBM maintenance.…”

Section: Discussionmentioning

confidence: 99%

Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells

Iglesia¹,

Prado

Cruz

et al. 2017

Stem Cell Res Ther

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BackgroundGlioblastoma (GBM), a highly aggressive brain tumor, contains a subpopulation of glioblastoma stem-like cells (GSCs) that play roles in tumor maintenance, invasion, and therapeutic resistance. GSCs are therefore a promising target for GBM treatment. Our group identified the cellular prion protein (PrPC) and its partner, the co-chaperone Hsp70/90 organizing protein (HOP), as potential target candidates due to their role in GBM tumorigenesis and in neural stem cell maintenance.MethodsGSCs expressing different levels of PrPC were cultured as neurospheres with growth factors, and characterized with stem cells markers and adhesion molecules markers through immunofluorescence and flow cytometry. We than evaluated GSC self-renewal and proliferation by clonal density assays and BrdU incorporation, respectively, in front of recombinant HOP treatment, combined or not with a HOP peptide which mimics the PrPC binding site. Stable silencing of HOP was also performed in parental and/or PrPC-depleted cell populations, and proliferation in vitro and tumor growth in vivo were evaluated. Migration assays were performed on laminin-1 pre-coated glass.ResultsWe observed that, when GBM cells are cultured as neurospheres, they express specific stemness markers such as CD133, CD15, Oct4, and SOX2; PrPC is upregulated compared to monolayer culture and co-localizes with CD133. PrPC silencing downregulates the expression of molecules associated with cancer stem cells, upregulates markers of cell differentiation and affects GSC self-renewal, pointing to a pivotal role for PrPC in the maintenance of GSCs. Exogenous HOP treatment increases proliferation and self-renewal of GSCs in a PrPC-dependent manner while HOP knockdown disturbs the proliferation process. In vivo, PrPC and/or HOP knockdown potently inhibits the growth of subcutaneously implanted glioblastoma cells. In addition, disruption of the PrPC-HOP complex by a HOP peptide, which mimics the PrPC binding site, affects GSC self-renewal and proliferation indicating that the HOP-PrPC complex is required for GSC stemness. Furthermore, PrPC-depleted GSCs downregulate cell adhesion-related proteins and impair cell migration indicating a putative role for PrPC in the cell surface stability of cell adhesion molecules and GBM cell invasiveness, respectively.ConclusionsIn conclusion, our results show that the modulation of HOP-PrPC engagement or the decrease of PrPC and HOP expression may represent a potential therapeutic intervention in GBM, regulating glioblastoma stem-like cell self-renewal, proliferation, and migration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0518-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells

Iglesia¹,

Prado

Cruz

et al. 2017

Stem Cell Res Ther

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“…In addition, overexpression of Hsp70 was shown to confer substantial heat resistance and protect cells and proteins from thermal damage via the efficient recognition of denatured proteins (46). By contrast, decreased Hsp70 levels were reported to have a reduced protective effect on myocardial cells (47).…”

Section: Discussionmentioning

confidence: 97%

Localization and expression of heat shock protein 70 with rat myocardial cell damage induced by heat stress in vitro and in vivo

Chen

Adam

Cheng

et al. 2014

Molecular Medicine Reports

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The aim of the present study was to investigate the association between heat shock protein (Hsp) 70 expression kinetics and heat stress‑induced damage to rat myocardial cells in vitro and in vivo. The results showed that the activity of heart injury‑associated enzymes, including aspartate aminotransferase and creatine kinase, significantly increased and myocardial cells developed acute histopathological lesions; this therefore suggested that heat stress altered the integrity of myocardial cells in vitro and in vivo. Levels of Hsp70 in vitro decreased following the initiation of heat stress and then steadily increased until heat stress ceased at 100 min; however, in vivo studies demonstrated a gradual increase in Hsp70 levels in the heart cells of rats from the initiation of heat stress, followed by a sharp decline at 100 min. These results indicated that the cells sustained different degrees of injury in vivo compared with those sustained in vitro, this may be due to different regulatory mechanisms in the two environments. Intracytoplasmic Hsp70 signaling was significantly reduced at 60 min in vitro, compared with that of the in vivo study, indicating that Hsp70 consumption may have exceeded its production prior to 60 min of heat stress, and following 60 min the cells produced sufficient Hsp70 protein for their protection against heat stress. Hsp70‑positive signals in the cytoplasm of heart cells in vivo were more prominent in the intact areas compared with those of the degenerated areas and the density of Hsp70‑positive signals was significantly reduced following 60 min of heat stress. In conclusion, comprehensive comparisons of enzymes, cell morphology and Hsp70 levels indicated that decreased levels of Hsp70 were associated with the reduced protective effect on myocardial cells in vitro and in vivo.

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“…The delivery of anti-HSP70 siRNA in glioblastoma, for instance, can significantly reduce HSP70 mRNA levels and sensitize cancer cells to chemotherapeutic agents. 60 Although commercial transfection agents such as Lipofectamine 2000®, HiPerFect®, or Superfect® have high efficiencies, it is at the cost of reduced cell viability. Collectively, the present polyamine dendrimers can be synthesized through innovative, economical and efficient steps, and can successfully deliver both plasmid DNA and siRNA in human cells with minimal cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

et al. 2016

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Low G1 generation polyamine dendrimers built around programmable, flexible, and short tetraethyleneglycol branches were readily prepared in a divergent manner using a combination of orthogonal AB 3 or AB 5 units and highly efficient chemical transformations based on Cu(I) catalyzed alkyne-azide cycloaddition (CUAAC) and thiol-ene click reactions. The constructs showed that the G1 polyamines with only twelve and eighteen amine surface groups can successfully deliver siRNA in human cells, with transfection efficiency comparable to that of Lipofectamine 2000®. Measurements of cell viability following transfection of plasmid DNA and siRNA showed that the dendritic polyamines are less cytotoxic than Lipofectamine 2000® and are thus preferable for biological applications.

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Hsp70 silencing with siRNA in nanocarriers enhances cancer cell death induced by the inhibitor of Hsp90

Cited by 42 publications

References 58 publications

Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells

Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells

Localization and expression of heat shock protein 70 with rat myocardial cell damage induced by heat stress in vitro and in vivo

Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

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