Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach

McConnell, Jeanette R.; Buckton, Laura K.; McAlpine, Shelli R.

doi:10.1016/j.bmcl.2015.06.052

Cited by 23 publications

(19 citation statements)

References 49 publications

(91 reference statements)

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“…Indeed, the dependence of AKT -overexpressing cells on HSF1 activity might render these cells susceptible to death induced by HSF1 inhibitors. In this regard, several HSF1 blockers have been developed and showed remarkable anti-tumor activity in numerous preclinical models [ 28 , 32 ]. In particular, a class of translation initiation inhibitors, known as rocaglates, has been proven to be extremely effective in suppressing HSF1 activity and to strongly constrain the growth of multiple cancer cell lines [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…The constructs used in the experiments, including pT3-EF1α-myr-AKT (HA-tagged) and pCMV/sleeping beauty transposase (SB), have been previously described [ 25 ]. The V5-tagged dominant negative form of human HSF1 (HSF1dn) [ 28 ] was cloned in a pT3-EF1α vector via Gateway cloning strategy. Plasmids were purified using the Endotoxin-free Maxi Prep Kit (Sigma-Aldrich, St. Louis, MO) before being injected into mice.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice

et al. 2017

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Upregulation of the heat shock transcription factor 1 (HSF1) has been described as a frequent event in many cancer types, but its oncogenic role in hepatocellular carcinoma (HCC) remains poorly delineated. In the present study, we assessed the function(s) of HSF1 in hepatocarcinogenesis via in vitro and in vivo approaches. In particular, we determined the importance of HSF1 on v-Akt murine thymoma viral oncogene homolog (AKT)-induced liver cancer development in mice. We found that knockdown of HSF1 activity via specific siRNA triggered growth restraint by suppressing cell proliferation and inducing massive cell apoptosis in human HCC cell lines. At the molecular level, HSF1 inhibition was accompanied by downregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade and related metabolic pathways. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery led to the inhibition of mouse hepatocarcinogenesis driven by overexpression of AKT. In human liver cancer specimens, we detected that HSF1 is progressively induced from human non-tumorous surrounding livers to HCC, reaching the highest expression in the tumors characterized by the poorest outcome (as defined by the length of patients’ survival). In conclusion, HSF1 is an independent prognostic factor in liver cancer and might represent an innovative therapeutic target in HCC subsets characterized by activation of the AKT/mTOR pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice

et al. 2017

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“…Thus HSF1 is released from its repressed association with Hsp90 [ 53 – 55 ], undergoes homotrimerization [ 41 ] and translocation to the nucleus, where it binds HSE [ 56 – 58 ]. However, as yet it is incapable of enhancing transcription and has minimal transactivation competence [ 59 – 64 ]. The next phase involves a series of phosphorylations that transforms the HSF1 trimer into an active transcription factor (reviewed in [ 34 , 35 ]).…”

Section: Activation Of Hsf1 and The Heat-shock Responsementioning

confidence: 99%

Mechanisms of Hsp90 regulation

Prodromou

2016

Biochemical Journal

248

197

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Heat shock protein 90 (Hsp90) is a molecular chaperone that is involved in the activation of disparate client proteins. This implicates Hsp90 in diverse biological processes that require a variety of co-ordinated regulatory mechanisms to control its activity. Perhaps the most important regulator is heat shock factor 1 (HSF1), which is primarily responsible for upregulating Hsp90 by binding heat shock elements (HSEs) within Hsp90 promoters. HSF1 is itself subject to a variety of regulatory processes and can directly respond to stress. HSF1 also interacts with a variety of transcriptional factors that help integrate biological signals, which in turn regulate Hsp90 appropriately. Because of the diverse clientele of Hsp90 a whole variety of co-chaperones also regulate its activity and some are directly responsible for delivery of client protein. Consequently, co-chaperones themselves, like Hsp90, are also subject to regulatory mechanisms such as post translational modification. This review, looks at the many different levels by which Hsp90 activity is ultimately regulated.

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“…In yeast and mammalian cells, Hsf1 is repressed by its interactions with Hsp70 chaperones. 73,103 In S. cerevisiae, derepression can occur by misfolded proteins titrating Ssa1 (Hsp70) away from Hsf1 75 or by chemicals binding to or oxidizing Ssa1 thiols, thereby removing/displacing chaperones from Hsf1. 57 Additional research will be required to determine which of these mechanisms, if any, applies to KP1019.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of the S. cerevisiae response to the anticancer ruthenium complex KP1019

et al. 2020

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Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach

Cited by 23 publications

References 49 publications

Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice

Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice

Mechanisms of Hsp90 regulation

Proteomic analysis of the S. cerevisiae response to the anticancer ruthenium complex KP1019

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