Hsp70 in cancer: back to the future

Sherman, Michael Y.; Gabai, Vladimir L.

doi:10.1038/onc.2014.349

Cited by 192 publications

(145 citation statements)

References 136 publications

(177 reference statements)

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“…The underlying molecular mechanisms on how to regulate the sensitivity of ovarian cancer cells to cisplatin by BAG3, a novel regulator of autophagy, have yet to be well characterized. BAG3 is constitutively expressed in myocytes and cancer cells derived from myeloid leukemias, neuroblastomas, prostate carcinomas, ovary and breast cancers, glioblastomas and other tumor tissues (28,29). However, in other nontransformed cells (for example epithelial and retinal cells), BAG3 expression can be induced by a variety of stressors, such as heavy metals or HIV infection (30).…”

Section: Discussionmentioning

confidence: 99%

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

et al. 2017

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Abstract. Ovarian cancer is the most lethal disease among all gynecological malignancies. Interval cytoreductive surgery and cisplatin-based chemotherapy are the recommended therapeutic strategies. However, acquired resistance to cisplatin remains a big challenge for the overall survival and prognosis in ovarian cancer. Complicated molecular mechanisms are involved in the process. At present, increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy. In the present study, as a novel autophagy regulator, BCL2-associated athanogene 3 (BAG3) was investigated to study its role in cisplatin sensitivity in epithelial ovarian cancer. However, whether BAG3 participates in cisplatin sensitivity by inducing autophagy and the underlying mechanism in ovarian cancer cells remain to be clarified. Through the use of quantitative real-time PCR, western blot analysis, CCK-8 and immunofluorescence assays our data revealed that cisplatin-induced autophagy protected ovarian cancer cells from the toxicity of the drug and that this process was regulated by BAG3. Silencing of BAG3 increased cisplatininduced apoptosis. The results also revealed BAG3 as a potential therapeutic target which enhanced the efficacy of cisplatin in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

et al. 2017

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“…Accumulating evidence indicates potent effects of HSP70 toward various diseases, such as cancer, infection and autoimmune diseases [4, 11]. Since the increase of HSP70 protein expression is reportedly related to poor outcome [12], it is currently considered that inhibition of HSP70 could become one of therapeutic targets against these diseases.…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein 70 Negatively Regulates TGF-β-Stimulated VEGF Synthesis via p38 MAP Kinase in Osteoblasts

Sakai

Tokuda

Fujita

et al. 2017

Cell Physiol Biochem

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Background/Aims: We previously demonstrated that transforming growth factor-β (TGF-β) stimulates the synthesis of vascular endothelial growth factor (VEGF) through the activation of p38 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. Heat shock protein70 (HSP70) is a ubiquitously expressed molecular chaperone. In the present study, we investigated the involvement of HSP70 in the TGF-β-stimulated VEGF synthesis and the underlying mechanism in these cells. Methods: Culture MC3T3-E1 cells were stimulated by TGF-β. Released VEGF was measured using an ELISA assay. VEGF mRNA level was quantified by RT-PCR. Phosphorylation of each protein kinase was analyzed by Western blotting. Results: VER-155008 and YM-08, both of HSP70 inhibitors, significantly amplified the TGF-β-stimulated VEGF release. In addition, the expression level of VEGF mRNA induced by TGF-β was enhanced by VER-155008. These inhibitors markedly strengthened the TGF-β-induced phosphorylation of p38 MAP kinase. The TGF-β-induced phosphorylation of p38 MAP kinase was amplified in HSP70-knockdown cells. SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by these inhibitors of the TGF-β-induced VEGF release. Conclusion: These results strongly suggest that HSP70 acts as a negative regulator in the TGF-β-stimulated VEGF synthesis in osteoblasts, and that the inhibitory effect of HSP70 is exerted at a point upstream of p38 MAP kinase.

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“…Both are overexpressed and considered to be oncogenic in different types of cancer, and their elevated expression is associated with a poor prognosis for cancer patients. Increased expression of both makes cancer cells resistant to cell death and chemotherapeutic drugs, and both have emerged as attractive targets of anticancer therapy (3,4,12,36). Altogether, according to the existing literature, both FOXM1 and HSP70 are oncogenes.…”

Section: Discussionmentioning

confidence: 99%

A Novel Function of Molecular Chaperone HSP70

Halasi¹,

Váraljai

Benevolenskaya

et al. 2016

Journal of Biological Chemistry

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The oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers, and it is a potential target for anticancer therapy. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Here we found that HSP90 inhibitor PF-4942847 and heat shock also suppress FOXM1. The common effector, which was induced after treatment with proteasome and HSP90 inhibitors or heat shock, was the molecular chaperone HSP70. We show that HSP70 binds to FOXM1 following proteotoxic stress and that HSP70 inhibits FOXM1 DNA-binding ability. Inhibition of FOXM1 transcriptional autoregulation by HSP70 leads to the suppression of FOXM1 protein expression. In addition, HSP70 suppression elevates FOXM1 expression, and simultaneous inhibition of FOXM1 and HSP70 increases the sensitivity of human cancer cells to anticancer drug-induced apoptosis. Overall, we determined the unique and novel mechanism of FOXM1 suppression by proteasome inhibitors.Forkhead Box M1 (FOXM1) is an oncogenic transcription factor that is also a well recognized cell cycle regulator (1). FOXM1 expression is eliminated from quiescent or differentiated cells, but it is highly expressed in proliferating and malignant cells (1). It is also well documented that FOXM1 is overexpressed in broad types of human cancers and it contributes to several aspects of cancer development (2, 3). Consequently, it is not surprising that FOXM1 has evolved as a potential target of anticancer therapy (4).Our group identified the thiazole antibiotics Siomycin A (5) and thiostrepton (6) as the first chemical inhibitors of FOXM1. Investigation of their mechanism of action revealed that they are proteasome inhibitors (7). Bona fide proteasome inhibitors, including MG132 and bortezomib, have also been found to hinder the transcriptional activity and expression of FOXM1 (7), suggesting that FOXM1 is one of the general targets of these drugs. Proteasome inhibitors stabilize the expression of cellular proteins. Therefore, suppression of FOXM1 is counterintuitive and has not been well understood. As an explanation for this effect, we put forward the hypothesis that a negative regulator of FOXM1 (NRFM) 2 is stabilized by proteasome inhibitors (8), which directly or indirectly inhibits FOXM1 transcriptional activity (9). Here we determined that the NRFM is HSP70. Because a positive autoregulation loop is required for FOXM1 expression (9), HSP70 (NRFM) also represses FOXM1 mRNA and protein expression after treatment with proteasome inhibitors.Heat shock proteins (HSPs) are stress proteins that are mainly expressed in response to different cellular and environmental insults. HSPs are divided by their molecular weight into the subfamilies HSP110, HSP90, HSP70, HSP60, and small HSPs. Besides their major function of aiding protein folding as molecular chaperones, HSPs also play important roles in cell signaling, protein trafficking, and blocking cell death (10 -13). Elevated levels of HSPs are linked not only to cytoprotection but to neurodegenerative ...

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Hsp70 in cancer: back to the future

Cited by 192 publications

References 136 publications

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

Heat Shock Protein 70 Negatively Regulates TGF-β-Stimulated VEGF Synthesis via p38 MAP Kinase in Osteoblasts

A Novel Function of Molecular Chaperone HSP70

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