Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

Im, Chang‐Nim; Yun, Hye Hyeon; Lee, Jeong-Hwa

doi:10.3390/ijms18020468

Cited by 18 publications

(9 citation statements)

References 38 publications

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“…It follows from the above data that the cancer stemness-related transcriptional activity of HSF1 is regulated via its phosphorylation/dephosphorylation; besides, proteins, such as FBXW7α [166] and BIS [168], can affect the relevant function and expression level of HSF1. Thus, there are several points for modulating HSF1's contribution to the formation/maintenance of the CSC phenotype.…”

Section: Hsf1 and Hsf1-activating Exposurementioning

confidence: 99%

“…By means of knockdown and overexpression of HSF1 in breast cancer cell lines, a direct contribution of this transcriptional factor to the CSC phenotype was demonstrated: The HSF1 expression level was positively correlated with the CSC phenotype frequency, stemness marker expression, and drug resistance [167]. HSF1 knockdown in sphere-forming human A172 glioblastoma CSCs resulted in failing of the spheroid-forming capacity, reduced expression of SOX2 (a marker of stemness), and downregulation of MMP2 activity; such an addiction of the glioblastoma CSC phenotype to HSF1 was somehow supported the Bcl-2-interacting cell death suppressor (BIS), as BIS depletion led to a decrease in the HSF1 protein level [168]. In a breast cancer model, it was shown how one of the key players in the CSC phenotype formation, β-catenin, is regulated by HSF1 in a phosphorylation-dependent manner: The activating phosphorylation of HSF1 at serine 326 led to HSF1-mediated involvement of the RNA-binding protein HuR (human antigen R), which controls β-catenin mRNA translation [169].…”

Section: Hsf1 and Hsf1-activating Exposurementioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Section: Hsf1 and Hsf1-activating Exposurementioning

confidence: 99%

Section: Hsf1 and Hsf1-activating Exposurementioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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“…TMZ is widely used to treat primary or metastatic brain cancer, which had efficacy on the recovery of patients . It was reported that BIS or HSF1 knockdown combined with TMZ treatment increased tumour apoptosis while cancer stem‐like properties was suppressed, such as SOX2 protein expression . Hao et al demonstrated that resveratrol combination with TMZ had significant efficacy on glioblastoma progression .…”

Section: Introductionmentioning

confidence: 99%

“…cancer stem-like properties was suppressed, such as SOX2 protein expression. 10 Hao et al demonstrated that resveratrol combination with TMZ had significant efficacy on glioblastoma progression. 11 Some studies also explored the effects of TMZ on glioblastoma cells activities.…”

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confidence: 99%

PLK1 inhibitor facilitates the suppressing effect of temozolomide on human brain glioma stem cells

Liu

Wang³

et al. 2018

J Cellular Molecular Medi

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Glioblastoma is the most frequent and most aggressive brain tumour in adults. Temozolomide is an oral chemotherapy drug and one of the major components of chemotherapy regimens used as a treatment of some brain cancers. We examined the tolerance of stem cells isolated from glioma cell line U87 and U251 to temozolomide (TMZ) and explored the effect of PLK1 (Polo like kinase 1) protein expression on TMZ sensibility. In our results, the inhibitory effects of TMZ on glioma cells U87, U251 and its stem cells were confirmed to be dose dependent and time dependent. Compared with glioma cells, the glioma stem cells showed a greater degree of tolerance. As the concentration of TMZ increased, the expression of PLK1 protein increased in U87 cells, CD133+ U87 stem cells and CD133‐ U87 cells. The increase range of PLK1 protein was large in CD133+ U87 stem cells and small in CD133‐ U87 cells. TMZ treatment in cells with low PLK1 protein expression efficiently suppressed the cell proliferation and sphere formation, while G2/M arrest was strongly induced. What's more, TMZ and PLK1 inhibitor synergize to inhibit glioma growth in vivo. In conclusion, our results suggest that down‐regulation of PLK1 protein enhanced the inhibition of TMZ on glioma stem cells, suggesting its clinical value to adverse TMZ resistance in glioma treatment.

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“…BIS was also shown to co-translocate into the nucleus with HSF1 upon heat shock stress in HeLa cells [ 38 ]. In addition, under glioblastoma stem cell like sphere-forming conditions, BIS depletion is known to decrease HSF1 protein levels and its nuclear localization [ 39 ]. Collectively, these results indicate that BIS might be positively involved in the nuclear translocation of HSF1.…”

Section: Discussionmentioning

confidence: 99%

Effect of BIS depletion on HSF1-dependent transcriptional activation in A549 non-small cell lung cancer cells

Yun

Baek

Seo

et al. 2018

Korean J Physiol Pharmacol

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The expression of BCL-2 interacting cell death suppressor (BIS), an anti-stress or anti-apoptotic protein, has been shown to be regulated at the transcriptional level by heat shock factor 1 (HSF1) upon various stresses. Recently, HSF1 was also shown to bind to BIS, but the significance of these protein-protein interactions on HSF1 activity has not been fully defined. In the present study, we observed that complete depletion of BIS using a CRISPR/Cas9 system in A549 non-small cell lung cancer did not affect the induction of heat shock protein (HSP) 70 and HSP27 mRNAs under various stress conditions such as heat shock, proteotoxic stress, and oxidative stress. The lack of a functional association of BIS with HSF1 activity was also demonstrated by transient downregulation of BIS by siRNA in A549 and U87 glioblastoma cells. Endogenous BIS mRNA levels were significantly suppressed in BIS knockout (KO) A549 cells compared to BIS wild type (WT) A549 cells at the constitutive and inducible levels. The promoter activities of BIS and HSP70 as well as the degradation rate of BIS mRNA were not influenced by depletion of BIS. In addition, the expression levels of the mutant BIS construct, in which 14 bp were deleted as in BIS-KO A549 cells, were not different from those of the WT BIS construct, indicating that mRNA stability was not the mechanism for autoregulation of BIS. Our results suggested that BIS was not required for HSF1 activity, but was required for its own expression, which involved an HSF1-independent pathway.

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Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

Cited by 18 publications

References 38 publications

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

PLK1 inhibitor facilitates the suppressing effect of temozolomide on human brain glioma stem cells

Effect of BIS depletion on HSF1-dependent transcriptional activation in A549 non-small cell lung cancer cells

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