Hsp90 Inhibitor STA9090 Sensitizes Hepatocellular Carcinoma to Hyperthermia-Induced DNA Damage by Suppressing DNA-PKcs Protein Stability and mRNA Transcription

Liu, Lixia; Deng, Yaotang; Zheng, Zhaoqiang; Deng, Zihao; Zhang, Jinxin; Li, Jieyou; Liang, Manfeng; Zhou, Xueqiong; Tan, Wenchong; Yang, Hongjun; Neckers, Leonard Μ.; Zou, Fei; Chen, Xuemei

doi:10.1158/1535-7163.mct-21-0215

Cited by 17 publications

(15 citation statements)

References 45 publications

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“…We also applied clonogenic survival assays to confirm that treatment is effective in a panel of 10 different cancer cell lines ( Figure 2 D), and that ganetespib can reduce the thermal dose and temperature required for sensitization ( Figure 3 C,D). These results are in line with multiple earlier studies relying on various inhibitors, treatment schedules and experimental models [ 44 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. It is thus clear that, at least in vitro, HSR disruption is an effective sensitization strategy.…”

Section: Conclusion and Future Perspectivessupporting

confidence: 91%

Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments

Scutigliani

Liang

IJff

et al. 2022

Cancers

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Hyperthermia is being used as a radio- and chemotherapy sensitizer for a growing range of tumor subtypes in the clinic. Its potential is limited, however, by the ability of cancer cells to activate a protective mechanism known as the heat stress response (HSR). The HSR is marked by the rapid overexpression of molecular chaperones, and recent advances in drug development make their inhibition an attractive option to improve the efficacy of hyperthermia-based therapies. Our previous in vitro work showed that a single, short co-treatment with a HSR (HSP90) inhibitor ganetespib prolongs and potentiates the effects of hyperthermia on DNA repair, enhances hyperthermic sensitization to radio- and chemotherapeutic agents, and reduces thermotolerance. In the current study, we first validated these results using an extended panel of cell lines and more robust methodology. Next, we examined the effects of hyperthermia and ganetespib on global proteome changes. Finally, we evaluated the potential of ganetespib to boost the efficacy of thermo-chemotherapy and thermo-radiotherapy in a xenograft murine model of cervix cancer. Our results revealed new insights into the effects of HSR inhibition on cellular responses to heat and show that ganetespib could be employed to increase the efficacy of hyperthermia when combined with radiation.

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Section: Conclusion and Future Perspectivessupporting

confidence: 91%

Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments

Scutigliani

Liang

IJff

et al. 2022

Cancers

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“…HSP90 is reported to be associated with and regulate SP1‐controlled gene transcription in hepatocarcinoma and lung cancer cells 34,35 . The regulation of SP1 on CRALBP's mRNA expression suggested that SP1 may act as a downstream transcriptional factor of HSP90 to regulate CRALBP transcriptional expression.…”

Section: Resultsmentioning

confidence: 99%

“…HSP90 has been shown to regulate multiple genes' transcription through interacting with different transcriptional factors, such as HSF1, P53, and SP1. 23,35,38 Our data indicate that SP1 is a client protein of HSP90 in RPE cells. It acts as a downstream of HSP90 to regulate CRALBP transcriptional expression.…”

Section: Discussionmentioning

confidence: 99%

“…HSP90 is reported to be associated with and regulate SP1controlled gene transcription in hepatocarcinoma and lung cancer cells. 34,35 The regulation of SP1 on CRALBP's mRNA expression suggested that SP1 may act as a downstream transcriptional factor of HSP90 to regulate CRALBP transcriptional expression. To do this, we performed an immunoprecipitation assay, and the results indicated that both endogenous HSP90α and HSP90β interacted with SP1 protein in ARPE-19 cells (Figure 4A,B, lane 2).…”

Section: Sp1 Protein Stabilization and Hsp90 And Sp1 Are Downregulate...mentioning

confidence: 99%

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The downregulation of HSP90‐controlled CRALBP expression is associated with age‐related vision attenuation

et al. 2023

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The dysfunction of CRALBP, a key regulator of the visual cycle, is associated with retinitis punctata albescens characterized by night vision loss and retinal degeneration. In this paper, we find that the expression of CRALBP is regulated by heat shock protein 90 (HSP90). Inhibition of HSP90α or HSP90β expression by using the CRISPR‐Cas9 technology downregulates CRALBP's mRNA and protein expression in ARPE‐19 cells by triggering the degradation of transcription factor SP1 in the ubiquitin–proteasome pathway. SP1 can bind to CRALBP's promoter, and inhibition of SP1 by its inhibitor plicamycin or siRNA downregulates CRALBP's mRNA expression. In the zebrafish, inhibition of HSP90 by the intraperitoneal injection of IPI504 reduces the thickness of the retinal outer nuclear layer and Rlbp1b mRNA expression. Interestingly, the expression of HSP90, SP1, and CRALBP is correlatedly downregulated in the senescent ARPE‐19 and Pig primary RPE cells in vitro and in the aged zebrafish and mouse retinal tissues in vivo. The aged mice exhibit the low night adaption activity. Taken together, these data indicate that the HSP90‐SP1 is a novel regulatory axis of CRALBP transcriptional expression in RPE cells. The age‐mediated downregulation of the HSP90‐SP1‐CRALBP axis is a potential etiology for the night vision reduction in senior people.

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“…The expression of SP1 is regulated by several transcription factors including STAT3 and RAD51, which are both affected by mistimed sleep here, and also by SP1 itself ( Tapias et al, 2008 ). Another glucocorticoid signalling component the heat shock protein HSP90AA1 is highly affected by mistimed sleep ( Figure 3 ) and also regulates SP1 activity such that inhibition of HSP90AA1 reduces SP1-mediated gene expression ( Liu et al, 2021 ). Thus, these mechanisms taken together may provide a framework by which mistimed sleep affects the expression of SP1 , the activity of SP1 protein as a transcription factor, and subsequent feedback to regulate its own expression.…”

Section: Discussionmentioning

confidence: 99%

Mistimed sleep and waking activity in humans disrupts glucocorticoid signalling transcripts and SP1, but not plasma cortisol rhythms

et al. 2022

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Cortisol is a robust circadian signal that synchronises peripheral circadian clocks with the central clock in the suprachiasmatic nucleus via glucocorticoid receptors that regulate peripheral gene expression. Misalignment of the cortisol rhythm with the sleep–wake cycle, as occurs in shift work, is associated with negative health outcomes, but underlying molecular mechanisms remain largely unknown. We experimentally induced misalignment between the sleep–wake cycle and melatonin and cortisol rhythms in humans and measured time series blood transcriptomics while participants slept in-phase and out-of-phase with the central clock. The cortisol rhythm remained unchanged, but many glucocorticoid signalling transcripts were disrupted by mistimed sleep. To investigate which factors drive this dissociation between cortisol and its signalling pathways, we conducted bioinformatic and temporal coherence analyses. We found that glucocorticoid signalling transcripts affected by mistimed sleep were enriched for binding sites for the transcription factor SP1. Furthermore, changes in the timing of the rhythms of SP1 transcripts, a major regulator of transcription, and changes in the timing of rhythms in transcripts of the glucocorticoid signalling pathways were closely associated. Associations between the rhythmic changes in factors that affect SP1 expression and its activity, such as STAT3, EP300, HSP90AA1, and MAPK1, were also observed. We conclude that plasma cortisol rhythms incompletely reflect the impact of mistimed sleep on glucocorticoid signalling pathways and that sleep–wake driven changes in SP1 may mediate disruption of these pathways. These results aid understanding of mechanisms by which mistimed sleep affects health.

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Hsp90 Inhibitor STA9090 Sensitizes Hepatocellular Carcinoma to Hyperthermia-Induced DNA Damage by Suppressing DNA-PKcs Protein Stability and mRNA Transcription

Cited by 17 publications

References 45 publications

Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments

Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments

The downregulation of HSP90‐controlled CRALBP expression is associated with age‐related vision attenuation

Mistimed sleep and waking activity in humans disrupts glucocorticoid signalling transcripts and SP1, but not plasma cortisol rhythms

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