Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines

Senju, Megumi; Sueoka, Naoko; Sato, Akemi; Iwanaga, Koichi; Sakao, Yukinori; Tomimitsu, Shinji; Tominaga, Masaki; Irie, Koji; Hayashi, Shinichiro; Sueoka, Eisaburo

doi:10.1007/s00432-005-0047-7

Cited by 65 publications

(50 citation statements)

References 33 publications

(46 reference statements)

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“…However, the effects of the Hsp90 inhibition are very complex and depend on the biochemical features and molecular background of treated cells [42]. The reported cell cycle effects are mostly G1 and G2/M arrest [43][44][45][46]. Here, after GA treatment of MCF-7 cells, we observed the increased incidence of apoptosis and the decreased frequency of polyploid cells with the features of mitotic catastrophe.…”

Section: Discussionsupporting

confidence: 48%

The alterations in SATB1 and nuclear F-actin expression affect apoptotic response of the MCF-7 cells to geldanamycin

Grzanka

Izdebska

Klimaszewska‐Wiśniewska

et al. 2015

Folia Histochem Cytobiol.

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Introduction. The function and localization of actin in the nucleus have not yet been fully described. However, actin seems to be a key protein in nuclear processes interacting with chromatin and matrix proteins. The aim of the study was to evaluate the effect of controlled expression of nuclear pool of F-actin and special AT-rich sequence-binding protein 1 (SATB1) on the in vitro induction of active cell death by geldanamycin (GA). Material and methods. The expression of SATB1 was regulated by the transfection of non-aggressive breast cancer MCF-7 cells with siRNA against SATB1 or expression plasmid with cloned cDNA of SATB1. The altered expression of cofilin-1 in these cells was used to regulate the nuclear expression and localization of F-actin. The effect of GA was analyzed in the context of cell death induction and cell cycle alterations. Results. Our studies revealed that the targeted regulation of SATB1 and cofilin-1 expression changed the apoptotic response of the MCF-7 cells to GA. The overexpression of these proteins potentiated GA-induced arrest of the cells in the G1 phase of cell cycle and increased the population of the hypodiploid cells. Conclusion. The alterations in the nuclear expression of SATB1 and F-actin in MCF-7 cells may affect their active cell death in response to GA.

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Section: Discussionsupporting

confidence: 48%

The alterations in SATB1 and nuclear F-actin expression affect apoptotic response of the MCF-7 cells to geldanamycin

Grzanka

Izdebska

Klimaszewska‐Wiśniewska

et al. 2015

Folia Histochem Cytobiol.

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“…A recent report has shown that GA and 17-AAG can cause a G 2 /M arrest that is associated with reduction of cdc25c and cdc2 in lung cancer cell lines (Senju et al, 2006). However, the authors did not study in detail the mechanism of downregulation of both cdc25c and cdc2 in these cell lines.…”

Section: Discussionmentioning

confidence: 95%

Inhibition of Hsp90 function by ansamycins causes downregulation of cdc2 and cdc25c and G2/M arrest in glioblastoma cell lines

et al. 2007

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Ansamycins exert their effects by binding heat shock protein 90 (Hsp90) and targeting important signalling molecules for degradation via the proteasome pathway. We wanted to study the effect of geldanamycin (GA) and its derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) on glioblastoma cell lines. We show that these cells are growth inhibited by ansamycins by being arrested in G 2 / M and, subsequently, cells undergo apoptosis. The protein levels of cell division cycle 2 (cdc2) kinase and cell division cycle 25c (cdc25c) were downregulated upon GA and 17-AAG treatment and cdc2 kinase activity was inhibited. However, other proteins involved in the G 2 /M checkpoint were not affected. The cdc2 and cdc25c mRNA levels did not show significant differences upon ansamycin treatment, but the stability of cdc2 protein was reduced. The association of cdc2 and cdc25c with p50 cdc37 , an Hsp90 cochaperone, decreased, but the interaction of cdc2 and cdc25c with the Hsp70 co-chaperone increased after ansamycin treatment. Proteasome inhibitors were able to rescue the cdc2 downregulation, but not the cdc25c reduction. However, calpain inhibitors were able to rescue the cdc25c downregulation, suggesting that cdc25c is proteolysed by calpains in the presence of ansamycins, and not by the proteasome. We conclude that ansamycins downregulate cdc2 and cdc25c by two different mechanisms.

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“…However, in many human tumor cells, by inhibiting apoptosis and promoting the proliferation of cancer cells, HSP90 facilitates the survival and growth of cancer cells [6][7][8]. The specific expression of HSP90 when acting as an anti-apoptotic chaperone protein is commonly higher in cancer cells, including prostate cancer [9], leukemia [10], and lung cancer [11]. HSP90B1 is a member of the HSP90 family of genes.…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein 90B1 Plays an Oncogenic Role and is a Target of microRNA-223 in Human Osteosarcoma

Cai

et al. 2012

Cell Physiol Biochem

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Background/Aims: Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer. However, the molecular mechanisms of down-regulation Hsp90 expression in osteosarcoma are incompletely understood. To develop potential therapy targeting Heat shock protein 90B1 (Hsp90B1), we studied the roles of miR- 223 in the proliferation and apoptosis of human osteosarcoma. Methods: pcDNA3.1(+)- miR-223 plasmid vectors were constructed and transfected into MG63 cells. Co-transfection of miR-223 expression vector with pMIR-Hsp90B1 (The recombined vector of pMIR-GLOTM luciferase vector containing Hsp90B1-3′UTR) led to the reduced activity of luciferase in a dual-luciferase reporter gene assay, suggesting that Hsp90B1 is a target gene of miR-223. Expression of HSP90B1 was detected by RT-PCR and western blotting analysis. Cell proliferation was determined using the MTT assay. Cell-cycle distribution and apoptosis were examined by flow cytometry. PI3K, p-Akt, Akt, mTOR, Bcl-2 and Bid were also detected by western blotting analysis. After a mouse xenograft model of human MG63 tumors was constructed, tumor growth, microvessel density and proliferation in each group was determined. Results: The pcDNA3.1(+)-miR-223 vector efficiently suppressed the expression of HSP90B1, while silencing miR-223 increased expression of Hsp90B1. Furthermore, overexpression of miR-223 results in significant inhibition of cell growth on culture plates. Moreover, cancer cells showed significant G0/G1 arrest and increased apoptosis due to gene silencing. Protein levels of PI3k, p-Akt, mTOR, and Bcl-2 were decreased, whereas Bid levels were increased. Microvessel density as assessed by CD34 levels and cell growth by PCNA levels decreased according to immunohistochemical analysis. Conclusion: Hsp90B1 is a direct target of miR-223 and miR- 223 may have a tumor suppressor function in osteosarcoma through the PI3K/Akt/mTOR pathway and could be used in anticancer therapies in osteosarcoma.

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Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines

Abstract: Hsp90 inhibitor is thus a therapeutic tool for lung cancer based on its target proteins, which are involved in tumor progression and antiproliferative activity in lung cancer cells.

Cited by 65 publications

References 33 publications

The alterations in SATB1 and nuclear F-actin expression affect apoptotic response of the MCF-7 cells to geldanamycin

The alterations in SATB1 and nuclear F-actin expression affect apoptotic response of the MCF-7 cells to geldanamycin

Inhibition of Hsp90 function by ansamycins causes downregulation of cdc2 and cdc25c and G2/M arrest in glioblastoma cell lines

Heat Shock Protein 90B1 Plays an Oncogenic Role and is a Target of microRNA-223 in Human Osteosarcoma

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