Inhibiting Heat Shock Factor 1 in Human Cancer Cells with a Potent RNA Aptamer

Salamanca, H. Hans; Antonyak, Marc A.; Cerione, Richard A.; Shi, Hua; Lis, John T.

doi:10.1371/journal.pone.0096330

Cited by 37 publications

(27 citation statements)

References 34 publications

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“…We had previously developed an RNA aptamer that interferes with the DNA binding of HSF1 [59] and inhibits HSF1 in human cancer cells [60]. Hsp70 also has oncogenic potential and its elimination has been shown to induce cancer cell death [61].…”

Section: Discussionmentioning

confidence: 99%

An RNA Aptamer Specific to Hsp70-ATP Conformation Inhibits its ATPase Activity Independent of Hsp40

Thirunavukarasu

Shi

2015

Nucleic Acid Therapeutics

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The highly conserved and ubiquitous molecular chaperone heat shock protein 70 (Hsp70) plays a critical role in protein homeostasis (proteostasis). Controlled by its ATPase activity, Hsp70 cycles between two conformations, Hsp70-ATP and Hsp70-ADP, to bind and release its substrate. Chemical tools with distinct modes of action, especially those capable of modulating the ATPase activity of Hsp70, are being actively sought after in the mechanistic dissection of this system. Here, we report a conformation-specific RNA aptamer that binds only to Hsp70-ATP but not to Hsp70-ADP. We have refined this aptamer and demonstrated its inhibitory effect on Hsp70's ATPase activity. We have also shown that this inhibitory effect on Hsp70 is independent of its interaction with the Hsp40 co-chaperone. As Hsp70 is increasingly being recognized as a drug target in a number of age related diseases such as neurodegenerative, protein misfolding diseases and cancer, this aptamer is potentially useful in therapeutic applications. Moreover, this work also demonstrates the feasibility of using aptamers to target ATPase activity as a general therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

An RNA Aptamer Specific to Hsp70-ATP Conformation Inhibits its ATPase Activity Independent of Hsp40

Thirunavukarasu

Shi

2015

Nucleic Acid Therapeutics

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“…We are motivated by both our results defining the essential function of Hsf1 in yeast, and other experiments that suggest that the effects of diminished HSF1 function in cancer cells expressing an anti-HSF1 RNA-aptamer can be rescued by Hsp70 or Hsp90 expression (Salamanca et al, 2014). The aforementioned CRISPRi strategy should also be amenable to testing whether the critical housekeeping role for HSF1 in mammalian cancers is confined to expression of the proteostasis factors we defined in untransformed cells.…”

Section: Chapter 4: Future Directionsmentioning

confidence: 99%

Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

Solís

Pandey

et al. 2018

Molecular Cell

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All rights reserved. I am especially thankful to my mom, dad and brother, all of whom were critical for getting me to grad school in the first place. I'm also forever thankful that they were always there to support and listen to me through my many struggles, even when the problems I was describing were unrelatable or unintelligibly described. know it would have been significantly less silly, ludicrous and off-putting to everyone else ix on the periphery if Patrick weren't down the hall from me, but I'm so glad I didn't have to live in that counterfactual universe. We have spent countless hours talking about science, politics, our personal lives, and many other things that I hope never get repeated, and I have enjoyed it all so very much.I have also been extremely fortunate for my academic advisors Vlad Denic and Edo Airoldi, along with my mentor and friend David Pincus. The three of them put an incredible amount of time into helping and guiding me as I grew as a scientist. When I reflect on the progress I've made since I started graduate school, I know that it would not have been possible without them constantly pushing me to be better. While it wasn't always fun or easy, I am so thankful for the time, energy and effort they put into me personally. They all went so far beyond what could reasonably be expected from an advisor, and even though all three were at challenging early stages of their own careers, they made an exceptional effort to help me as I started my own. I will always be thankful and grateful to Edo, Vlad and Dave for molding me into the scientist that I am today. In order to adapt when stress causes the folding environment to deteriorate, cells need a mechanism to adjust the availability of chaperones according to need. One simple mechanism employed by some bacteria to regulate expression of chaperones during heat shock involves RNA secondary structure that occludes the ribosome binding site at low 2 temperatures, but melts at high temperature de-repressing translation during thermal stress (Cimdins et al., 2014). However, rather than regulating each chaperone gene individually, eukaryotic cells have evolved a highly conserved feedback mechanism that coordinates up-regulation of many proteostasis factors in response to stress. The first indication of this mechanism were made by Ferruccio Ritossa in 1962 when he noticed a novel pattern of "puffs" on the polytene salivary gland chromosomes of Drosophila larvae that were subjected to a serendipitous heat shock when a co-worker increased their incubator's temperature (Ritossa, 1996). Subsequent controlled experiments revealed that shifting larvae from 25°C to 30°C caused puffs that were stable at the lower temperature to rapidly dissipate and induced the appearance of novel, reproducible puffs (Ritossa, 1962). It was soon revealed that the temperature stress caused by the actions of an unwitting co-worker has spurred the first observation of the dramatic changes in gene expression that comprise the heat shock response.It was subsequently revealed tha...

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“…Heat Shock Factor 1 (HSF1), the master regulator of the response to the heat, in cancer cells has a specific transcriptional signature that enhances malignancy 64. Inhibition of the HSF1 by an RNA aptamer in cancer cells induced apoptosis and abolished their colony‐forming capability 65. The above results speak in favour of therapeutic inhibition of the HSPs.…”

Section: Discussionmentioning

confidence: 99%

Influence of hyperthermal regimes on experimental teratoma development in vitro

Bojanac

Rogosic

Sinčić

et al. 2018

Int J Experimental Path

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SummaryWe screened for the impact of hyperthermal regimes varying in the cumulative equivalent minutes at 43°C (CEM43°C) and media composition on tumour development using an original teratoma in vitro model. Rat embryos (three germ layers) were microsurgically isolated and cultivated at the air‐liquid interface. During a two week period, ectodermal, mesodermal and endodermal derivatives developed within trilaminar teratomas. Controls were grown at 37°C. Overall growth was measured, and teratoma survival and differentiation were histologically assessed. Cell proliferation was stereologically quantified by the volume density of Proliferating Cell Nuclear Antigen. Hyperthermia of 42°C, applied for 15 minutes after plating (CEM43°C 3.75 minutes), diminished cell proliferation (P ˂ .0001) and enhanced differentiation of both myotubes (P ˂ .01) and cylindrical epithelium (P ˂ .05). Hyperthermia of 43°C applied each day for 30 minutes during the first week (CEM43°C 210 minutes) impaired overall growth (P ˂ .01) and diminished cell proliferation (P ˂ .0001). Long‐term hyperthermia of 40.5°C applied for two weeks (CEM43°C 630 minutes) significantly impaired survival (P ˂ .005). Long‐term hyperthermia of 40.5°C applied from the second day when differentiation of tissues begins (CEM43°C 585 minutes) impaired survival (P ˂ .0001), overall growth (P ˂ .01) and cartilage differentiation (P ˂ .05). No teratomas survived extreme regimes: 43°C for 24 hours (CEM43°C 1440 minutes), hyperthermia in the scant serum‐free medium (CEM43°C 630 minutes) or treatment with an anti‐HSP70 antibody before long‐term hyperthermia 40.5°C from the second day (CEM43°C 585 minutes). This in vitro research provided novel insights into the impact of hyperthermia on the development of experimental teratomas from their undifferentiated sources and are thus of potential interest for future therapeutic strategies in corresponding in vivo models.

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Inhibiting Heat Shock Factor 1 in Human Cancer Cells with a Potent RNA Aptamer

Cited by 37 publications

References 34 publications

An RNA Aptamer Specific to Hsp70-ATP Conformation Inhibits its ATPase Activity Independent of Hsp40

An RNA Aptamer Specific to Hsp70-ATP Conformation Inhibits its ATPase Activity Independent of Hsp40

Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

Influence of hyperthermal regimes on experimental teratoma development in vitro

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