Cancerous phenotypes associated with hypoxia-inducible factors are not influenced by the volatile anesthetic isoflurane in renal cell carcinoma

Sumi, Chisato; Matsuo, Yoshiyuki; Kusunoki, Munenori; Shoji, Tomohiro; Uba, Takeo; Iwai, Teppei; Bono, Hidemasa; Hirota, Kiichi

doi:10.1101/375311

Cited by 5 publications

(6 citation statements)

References 28 publications

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“…Supporting HIF2α involvement in ccRCC migration, RCC4 VHL cells migrated more than RCC4 WT, in contrast to previous publications 33,34 . In this case, as they also express HIF1α, both HIF2α and HIF1α could be inhibiting cell migration; however, treatment with PT2385 generated an intermediate phenotype pointing to a more important role of HIF2α.…”

Section: Discussioncontrasting

confidence: 91%

“…On the other hand, PT2385 treatment showed that DNA binding is not completely abolished by the inhibitor, as previously reported 22 , as cell invasion was not 100% suppressed. Supporting HIF2α involvement in ccRCC migration, RCC4 VHL cells migrated more than RCC4 WT, in contrast to previous publications 33,34 . In this case, as they also express HIF1α, both HIF2α and HIF1α could be inhibiting cell migration; however, treatment with PT2385 generated an intermediate phenotype pointing to a more important role of HIF2α.…”

Section: Discussioncontrasting

confidence: 91%

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Differential Effects of HIF2α Antagonist and HIF2α Silencing in Renal Cancer and Sensitivity to Repurposed Drugs

Arnaiz

Miar

Bridges

et al. 2021

Preprint

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Background: in clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods: we assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385. Results: PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

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Section: Discussioncontrasting

confidence: 91%

Section: Discussioncontrasting

confidence: 91%

Differential Effects of HIF2α Antagonist and HIF2α Silencing in Renal Cancer and Sensitivity to Repurposed Drugs

Arnaiz

Miar

Bridges

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Total RNA was processed with a TruSeq Stranded mRNA sample prep kit (Illumina, San Diego, CA, USA) (Sumi et al, 2019). Poly(A) RNA libraries were then constructed using the TruSeq Stranded mRNA library preparation kit (Illumina) and sequenced in 100-bp paired-end reads on an Illumina NovaSeq6000 platform (Sumi et al, 2019). RNA-Seq was performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Inhibiting SARS-CoV-2 infectionin vitroby suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

Tanimoto

Hirota

Fukazawa

et al. 2021

Preprint

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Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including CSE, FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.

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“…29 . Poly(A) RNA libraries were then constructed using the TruSeq Stranded mRNA www.nature.com/scientificreports/ library preparation kit (Illumina) and sequenced in 100-bp paired-end reads on an Illumina NovaSeq6000 platform 30 . RNA-Seq was performed in triplicate.…”

Section: Quantitative Reverse Transcription-polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

Tanimoto

Hirota

Fukazawa

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.

show abstract

Cancerous phenotypes associated with hypoxia-inducible factors are not influenced by the volatile anesthetic isoflurane in renal cell carcinoma

Cited by 5 publications

References 28 publications

Differential Effects of HIF2α Antagonist and HIF2α Silencing in Renal Cancer and Sensitivity to Repurposed Drugs

Differential Effects of HIF2α Antagonist and HIF2α Silencing in Renal Cancer and Sensitivity to Repurposed Drugs

Inhibiting SARS-CoV-2 infectionin vitroby suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal

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