Concerted actions of multiple transcription elements confer differential transactivation of HSP90 isoforms in geldanamycin‐treated 9L rat gliosarcoma cells

Chao, Chih-Chung; Sun, Fei; Wang, Chih-Hsiang; Lo, Chih-Wei; Chang, Yuo-Sheng; Chang, Kun-Che; Chang, Margaret Dah-Tysr; Lai, Yiu‐Kay

doi:10.1002/jcb.21705

Cited by 7 publications

(7 citation statements)

References 46 publications

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“…K562 erythroleukemic or rat 9L gliosarcoma cells [19], [21]. GA-induced upregulation of Hsp70 has been recently linked to chemotherapy resistance [15], [26]–[28].…”

Section: Resultsmentioning

confidence: 99%

“…However, very little is known about GA impact on modulation of HSPs expression, and potential correlation with chemotherapy effectiveness. It seems that GA influences HSPs expression by the stabilization of the transcription factor HSF1 trimeric complex with heat shock response element (HSE), and thus stimulates the expression of HSPs coding genes [19]–[21]. The therapeutic usage of GA has been limited mainly due to hepatotoxicity, however, less toxic GA analogs (17AAG, 17DMAG) have been developed, and extensively tested [22]–[24].…”

Section: Introductionmentioning

confidence: 99%

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Geldanamycin-Induced Osteosarcoma Cell Death Is Associated with Hyperacetylation and Loss of Mitochondrial Pool of Heat Shock Protein 60 (Hsp60)

et al. 2013

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Osteosarcoma is one of the most malignant tumors of childhood and adolescence that is often resistant to standard chemo- and radio-therapy. Geldanamycin and geldanamycin analogs have been recently studied as potential anticancer agents for osteosarcoma treatment. Here, for the first time, we have presented novel anticancer mechanisms of geldanamycin biological activity. Moreover, we demonstrated an association between the effects of geldanamycin on the major heat shock proteins (HSPs) and the overall survival of highly metastatic human osteosarcoma 143B cells. We demonstrated that the treatment of 143B cells with geldanamycin caused a subsequent upregulation of cytoplasmic Hsp90 and Hsp70 whose activity is at least partly responsible for cancer development and drug resistance. On the other hand, geldanamycin induced upregulation of Hsp60 gene expression, and a simultaneous loss of hyperacetylated Hsp60 mitochondrial protein pool resulting in decreased viability and augmented cancer cell death. Hyperacetylation of Hsp60 seems to be associated with anticancer activity of geldanamycin. In light of the fact that mitochondrial dysfunction plays a critical role in the apoptotic signaling pathway, the presented data may support a hypothesis that Hsp60 can be another functional part of mitochondria-related acetylome being a potential target for developing novel anticancer strategies.

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“…K562 erythroleukemic or rat 9L gliosarcoma cells [19], [21]. GA-induced upregulation of Hsp70 has been recently linked to chemotherapy resistance [15], [26]–[28].…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Geldanamycin-Induced Osteosarcoma Cell Death Is Associated with Hyperacetylation and Loss of Mitochondrial Pool of Heat Shock Protein 60 (Hsp60)

et al. 2013

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“…GA acts as an inhibitor of the Hsp90 function, but also as an inducer of heat-shock genes, including the Hsp90 gene. Moreover, GA can induce expression of many stress proteins, such as GRPs and Hsp90s, in a concentration-dependent and cell-specific manner (31,32). Despite its influence on the Hsp90 function and expression of heat-shock genes and proteins, the distinct mechanism of action of GA is associated with the induction of oxidative stress and production of reactive oxygen species (ROS) related to its quinone group (33).…”

Section: Geldanamycin and Its Derivativesmentioning

confidence: 99%

Geldanamycin and its derivatives as Hsp90 inhibitors

Górska

Popowska²,

Sielicka-Dudzin³

et al. 2012

Front Biosci

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The Hsp90 molecule, one of the most abundant heat shock proteins in mammalian cells, maintains homeostasis and prevents stress-induced cellular damage. Hsp90 is expressed under normal conditions at a level of about 1-2 Percent of total proteins, while its expression increases 2-10 fold in cancer cells. The two main constitutively expressed isoforms of Hsp90 are known as Hsp90-alpha and Hsp90-beta, and their upregulation is associated with tumor progression, invasion and formation of metastases, as well as development of drug resistance. The Hsp90 is a key target for many newly established, potent anticancer agents containing Hsp90 N-terminal ATP binding inhibitors, such as geldanamycin, and its analogues 17AAG and 17DMAG. The therapeutic usage of geldanamycin has been limited due to its poor water solubility and severe hepatotoxicity. Therefore, its analogues, including 17AAG, 17DMAG, Tanespimycin and Retaspimycin hydrochloride, with improved pharmacokinetic profiles, have been developed.

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“…Currently, there are no studies concerning impact of different Hsp90 isoforms on activity of nNOS. As suggested by Chao et al, it could be due to specific SDS-PAGE conditions [65].…”

Section: Discussionmentioning

confidence: 93%

The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model

Górska‐Ponikowska

Kuban–Jankowska

Gammazza

et al. 2020

IJMS

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2-Methoxyestradiol is one of the natural 17β-estradiol derivatives and a potential novel anticancer agent currently being under evaluation in advanced phases of clinical trials. However, the mechanism of anticancer action of 2-methoxyestradiol has not been yet fully established. In our previous studies we have demonstrated that 2-methoxyestradiol selectively induces the expression and nuclear translocation of neuronal nitric oxide synthase in osteosarcoma 143B cells. Heat shock proteins (Hsps) are factors involved in the regulation of expression and activity of nitric oxide synthases. Herein, we chose osteosarcoma cell lines differed in metastatic potential, metastatic 143B and highly metastatic MG63.2 cells, in order to further investigate the anticancer mechanism of 2-methoxyestradiol. The current study aimed to determine the role of major heat shock proteins, Hsp90 and Hsp70 in 2-methoxyestradiol-induced osteosarcoma cell death. We focused on the implication of Hsp90 and Hsp70 in control under expression of neuronal nitric oxide synthase, localization of the enzyme, and further generation of nitro-oxidative stress. To give the insight into the role of Hsp90 in regulation of anticancer efficacy of 2-methoxyestradiol, we used geldanamycin as a potent Hsp90 inhibitor. Herein, we evidenced that inhibition of Hsp90 controls the protein expression of 2-methoxyestradiol-induced neuronal nitric oxide synthase and inhibits enzyme nuclear translocation. We propose that decreased level of neuronal nitric oxide synthase protein after a combined treatment with 2-methoxyestradiol and geldanamycin is directly associated with the accompanying upregulation of Hsp70 and downregulation of Hsp90. This interaction resulted in abrogation of anticancer efficacy of 2-methoxyestradiol by geldanamycin.

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Concerted actions of multiple transcription elements confer differential transactivation of HSP90 isoforms in geldanamycin‐treated 9L rat gliosarcoma cells

Cited by 7 publications

References 46 publications

Geldanamycin-Induced Osteosarcoma Cell Death Is Associated with Hyperacetylation and Loss of Mitochondrial Pool of Heat Shock Protein 60 (Hsp60)

Geldanamycin-Induced Osteosarcoma Cell Death Is Associated with Hyperacetylation and Loss of Mitochondrial Pool of Heat Shock Protein 60 (Hsp60)

Geldanamycin and its derivatives as Hsp90 inhibitors

The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model

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