Radioresistance is associated to increased Hsp70 content in human glioblastoma cell lines

Rocha, Adriana Brondani da; Regner, Andréa; Grivicich, Ivana; Schunemann, Daniel Pretto; Diel, Celito Luis; Kovaleski, Giovana; Farias, Caroline Brunetto de; Mondadori, Edlaine; Almeida, Leonardo; Filho, Aroldo Braga; Schwartsmann, Gilberto

doi:10.3892/ijo.25.3.777

Cited by 48 publications

(42 citation statements)

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“…We selected the GBM cell line U87MG which is a relatively radioresistant cell line, in which apoptosis is not triggered until 72 h (1). First, radiosensitivity was tested to determine the radiation dose.…”

Section: Discussionmentioning

confidence: 99%

“…Radiotherapy, with or without surgery, is the cornerstone of the treatment plan for this tumor. However, the radiotherapeutic efficiency is often limited by the occurrence of radioresistance, reflected as a diminished susceptibility of the irradiated cells to undergo apoptosis (1). As a result, this therapeutic strategy can not substantially improve the survival rate .…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2

Chen

Zhu²,

Shi³

et al. 2010

Oncol Rep

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Abstract. Radiotherapy is widely used in cancer treatment and biological studies. Multiple mechanisms induced by radiation, especially changes of the expression profile of genes, lead to the disruption of cellular homeostasis. MicroRNAs (miRNAs) are important post-transcriptional gene regulators and play an important role in response to cellular stress. Here we investigated the profiles of miRNA expression following exposure to radiation and the possible role of miRNAs in the modulation of radiosensitivity in the glioblastoma multiform U87MG cell line. MiRNA expression profiles revealed a limited set of miRNAs with altered expression in U87MG cells in response to radiation treatment. MiR-181a, a member of miR-181 family, was one of the down-regulated miRNAs, whose expression was further validated by qRT-PCR. The target mRNAs of radiation-responsive miRNAs were predicted with a target prediction tool. Transiently overexpressed miR-181a significantly sensitized malignant glioma cells to radiation treatment concurrent with the downregulation of the protein Bcl-2 (B cell lymphoma/lewkmia-2). It indicates that miR-181a may modulate radiosensitivity by targeting Bcl-2 in human malignant glioma cells. These data suggest that radiation can affect miRNA expression, which regulates the cellular response, and miR-181a could be a target for enhancing the effect of radiation treatment on malignant glioma cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2

Chen

Zhu²,

Shi³

et al. 2010

Oncol Rep

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“…Moreover, CRT regulates p53 function to induce apoptosis by affecting the rate of degradation and nuclear localization of p53 (12). Furthermore, there have been few reports related to the molecular chaperones and radiation-induced apoptosis of glioma (22). However, it is still not clear whether CRT is involved in the regulatory mechanism for the radiation-induced apoptosis.…”

Section: Introductionmentioning

confidence: 98%

Calreticulin, a Molecular Chaperone in the Endoplasmic Reticulum, Modulates Radiosensitivity of Human Glioblastoma U251MG Cells

Okunaga

Urata²,

Goto³

et al. 2006

Cancer Research

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Radiotherapy is the primary and most important adjuvant therapy for malignant gliomas. Although the mechanism of radiation resistance in gliomas has been studied for decades, it is still not clear how the resistance is related with functions of molecular chaperones in the endoplasmic reticulum. Calreticulin (CRT) is a Ca 2+ -binding molecular chaperone in the endoplasmic reticulum. Recently, it was reported that changes in intracellular Ca 2+ homeostasis play a role in the modulation of apoptosis. In the present study, we found that the level of CRT was higher in neuroglioma H4 cells than in glioblastoma cells (U251MG and T98G), and was well correlated with the sensitivity to ;-irradiation. To examine the role of CRT in the radiosensitivity of malignant gliomas, the CRT gene was introduced into U251MG cells, which express low levels of CRT, and the effect of overexpression of CRT on the radiosensitivity was examined. The cells transfected with the CRT gene exhibited enhanced radiationinduced apoptosis compared with untransfected control cells. In CRT-overexpressing cells, cell survival signaling via Akt was markedly suppressed. Furthermore, the gene expression of protein phosphatase 2AcA (PP2AcA), which is responsible for the dephosphorylation and inactivation of Akt, was up-regulated in CRT-overexpressing cells, and the regulation was dependent on Ca 2+. Thus, overexpression of CRT modulates radiation-induced apoptosis by suppressing Akt signaling through the up-regulation of PP2AcA expression via altered Ca 2+ homeostasis. These results show the novel mechanism by which CRT is involved in the regulation of radiosensitivity and radiation-induced apoptosis in malignant glioma cells.

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“…HSP70 up-regulation, as a consequence of either oncogenic transformation or cellular stress, may inhibit apoptosis induced by a wide range of cellular insults, as suggested by transfection experiments in vitro (16,21). HSP70 overexpression in cancer cells also increases their tumorigenicity in rodent models (22), and high HSP70 expression in human breast cancer, glioblastoma, endometrial, or renal tumors has been associated with metastasis, poor prognosis, and resistance to chemotherapy or radiation therapy (23)(24)(25)(26)(27)(28). The down-regulation of HSP70 can be sufficient to kill tumor cells or to sensitize them to cytotoxic druginduced apoptosis in vitro and to decrease their tumorigenicity in vivo (29,30).…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein 70 Neutralization Exerts Potent Antitumor Effects in Animal Models of Colon Cancer and Melanoma

et al. 2006

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When overexpressed, the stress protein heat shock protein 70 (HSP70) increases the oncogenic potential of cancer cells in rodent models. HSP70 also prevents apoptosis, thereby increasing the survival of cells exposed to a wide range of otherwise lethal stimuli. These protective functions of HSP70 involve its interaction with and neutralization of the adaptor molecule apoptotic protease activation factor-1, implicated in caspase activation, and the flavoprotein apoptosis-inducing factor (AIF), involved in caspase-independent cell death. We have shown previously that a peptide containing the AIF sequence involved in its interaction with HSP70 (ADD70, amino acids 150-228) binds to and neutralizes HSP70 in the cytosol, thereby sensitizing cancer cells to apoptosis induced by a variety of death stimuli. Here, we show that expression of ADD70 in tumor cells decreases their tumorigenicity in syngeneic animals without affecting their growth in immunodeficient animals. ADD70 antitumorigenic effects are associated with an increase in tumor-infiltrating cytotoxic CD8 + T cells. In addition, ADD70 sensitizes rat colon cancer cells (PROb) and mouse melanoma cells (B16F10) to the chemotherapeutic agent cisplatin. ADD70 also shows an additive effect with HSP90 inhibition by 17-allylamino-17-demethoxygeldanamycin in vitro. Altogether, these data indicate the potential interest of targeting the HSP70 interaction with AIF for cancer therapy.

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Radioresistance is associated to increased Hsp70 content in human glioblastoma cell lines

Cited by 48 publications

References 0 publications

MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2

MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2

Calreticulin, a Molecular Chaperone in the Endoplasmic Reticulum, Modulates Radiosensitivity of Human Glioblastoma U251MG Cells

Heat Shock Protein 70 Neutralization Exerts Potent Antitumor Effects in Animal Models of Colon Cancer and Melanoma

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