Enhancement of complement-induced cell lysis: a novel mechanism for the anticancer effects of Hsp90 inhibitors

Sreedhar, Amere Subbarao; Nardai, Gábor; Csermely, Péter

doi:10.1016/j.imlet.2003.11.025

Cited by 22 publications

(12 citation statements)

References 37 publications

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“…It influences the activity of many client proteins that function as critical regulators of cellular growth, differentiation, and apoptotic pathways (1–5). Hsp90 client proteins include oncogenic proteins in human malignancies acting via multiple signal transduction pathways: steroid receptors, epidermal growth factor receptor family members, MET, Raf-1 kinase, AKT, Bcr-abl, mutant p53, CDK4, and many other molecules (6–8).…”

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confidence: 99%

Heat Shock Protein 90 Is Critical for Regulation of Phenotype and Functional Activity of Human T Lymphocytes and NK Cells

Bae

Munshi

Cheng

et al. 2013

The Journal of Immunology

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The 90-kDa heat shock protein (Hsp90) has become an important therapeutic target with ongoing evaluation in a number of malignancies. Although Hsp90 inhibitors have a high therapeutic index with limited effects on normal cells, they have been described to inhibit dendritic cell function. However, its effect on human immune effector cells may have significant clinical implications, but remains unexplored. In this study, we have evaluated the effects of Hsp90 inhibition on human T lymphocyte and NK cells, including their Ag expression, activation, proliferation, and functional activities. These studies demonstrate that Hsp90 inhibition irreversibly downregulates cell surface expression of critical Ags (CD3, CD4, CD8), the costimulatory molecule (CD28, CD40L), and αβ receptors on T lymphocytes, as well as activating receptors (CD2, CD11a, CD94, NKp30, NKp44, NKp46, KARp50.3) on NK cells. Hsp90 inhibition significantly reduced CD4 protein expression on T lymphocytes at both the cell surface and intracellular level, which was shown to be associated with aberrant regulation of Src-kinase p56Lck. Downregulation of the Ags triggered by Hsp90 inhibition on CD3+ T lymphocytes, both in CD4+ and CD8+ T cell subsets, was associated with a disruption in their cellular activation, proliferation, and/or IFN-γ production, when the inhibition occurred either in activated or inactivated cells. In addition, downregulation of key activating receptors on NK cells following Hsp90 inhibition resulted in decreased cytotoxicity against tumor cells. Therefore, these observations demonstrate the need to closely monitor immune function in patients being treated with a Hsp90 inhibitor and may provide a potential therapeutic application in autoimmune diseases.

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confidence: 99%

Heat Shock Protein 90 Is Critical for Regulation of Phenotype and Functional Activity of Human T Lymphocytes and NK Cells

Bae

Munshi

Cheng

et al. 2013

The Journal of Immunology

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“…Studies involving experimental exposure to electromagnetic fields have revealed numerous modifications in the expression of heat shock proteins in vivo [8] and in vitro, in cell lines [9]. HSP-90 is the most common type of heat shock protein [10] and occurs at higher levels in nerve tissues than in non nerve tissues [11] and is distributed in neurons in the limbic system, neocortex, striatus and thalamus [12,13]. This protein acts to regulate the activity of other proteins such as steroid hormone receptors [14] kinase [15], calmodulin [16], actin [17], and tubulin [18].…”

Section: Introductionmentioning

confidence: 99%

EXPOSURE TO 2.45 GHz MICROWAVE RADIATION PROVOKES CEREBRAL CHANGES IN INDUCTION OF HSP-90 Î±/Î² HEAT SHOCK PROTEIN IN RAT.

Jorge-Mora¹,

Álvarez-Folgueiras²,

Leiro³

et al. 2010

PIER

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Abstract-Physical agents such as non-ionizing continuous-wave 2.45 GHz radiation may cause damage that alters cellular homeostasis and may trigger activation of the genes that encode heat shock proteins (HSP). We used Enzyme-Linked ImmunoSorbent Assay (ELISA) and immunohistochemistry to analyze the changes in levels of HSP-90 and its distribution in the brain of Sprague-Dawley rats, ninety minutes and twenty-four hours after acute (30min) continuous exposure to 2.45 GHz radiation in a the Gigahertz Transverse Electromagnetic (GTEM cell). In addition, we studied further indicators of neuronal insult: dark neurons, chromatin condensation and nucleus fragmentation, which were observed under optical conventional or fluorescence microscopy after DAPI staining. The cellular distribution of protein HSP-90 in the brain increased with each corresponding SAR (0.034 ± 3.10 −3 , 0.069 ± 5.10 −3 , 0.27 ± 21.10 −3 W/kg), in hypothalamic nuclei, limbic cortex and somatosensorial cortex after exposure to the radiation. At twenty-four hours post-irradiation, levels of HSP-90 protein remained high in all hypothalamic nuclei for all SARs, and in the parietal cortex, except the limbic system, HSP-90 levels were lower than in non-irradiated rats, almost half the levels in rats exposed to the highest power radiation. Non-apoptotic cellular nuclei and a some dark neurons were found ninety minutes and twenty-four hours after maximal SAR exposure. The results suggest that acute exposure to electromagnetic fields triggered an imbalance in anatomical HSP-90 levels but the anti-apoptotic mechanism is probably sufficient to compensate the non-ionizing stimulus. Further studies are required to determine the regional effects of chronic electromagnetic pollution on heat shock proteins and their involvement in neurological processes and neuronal damage.

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“…5 HSPs play a pivotal role in protecting cells from apoptosis, thereby prolonging survival. [3][4][5][6][7] In recent years, the molecular chaperone that has emerged as the most promising target of innovative cancer therapy is HSP90. HSP90 is ubiquitously expressed in the cytoplasm of normal cells where it binds with many client proteins and is involved in homeostasis.…”

mentioning

confidence: 99%

“…HSP90 is ubiquitously expressed in the cytoplasm of normal cells where it binds with many client proteins and is involved in homeostasis. [1][2][3][4][5][6][7] In normal cells, HSP90 is expressed at relatively low levels and does not form complexes with other chaperone proteins. 8 Thus, others have suggested that HSP90 is present in latent form in normal cells.…”

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confidence: 99%

Expression of heat-shock protein-90 in non-Hodgkin's lymphomas

et al. 2005

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Heat-shock protein-90 (HSP90) inhibitors are currently being used in phase I clinical trials for treating patients with a variety of neoplasms including lymphomas. Using immunohistochemical methods, we assessed for HSP90 expression in 412 cases of non-Hodgkin's lymphoma. In B-cell lymphomas, HSP90 was moderately to strongly expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in subsets of follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). HSP90 was weakly expressed in six of 14 (43%) cases of extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue. In T-cell lymphomas, HSP90 was moderately to strongly expressed in subsets of anaplastic large-cell lymphoma (14/24, 58%; 9/12 ALK þ and 5/12 ALKÀ), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%) and angioimmunoblastic T-cell lymphoma (2/17, 12%). HSP90 was weakly expressed in seven of 58 (12%) cases of mycosis fungoides. We conclude that HSP90 is commonly expressed in a subset of many types of B-and T-cell lymphoma. These data suggest that many lymphoma types are suitable targets for modulation of HSP90 activity, and that HSP90 inhibitors are a potential investigational therapy for lymphoma patients.

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Enhancement of complement-induced cell lysis: a novel mechanism for the anticancer effects of Hsp90 inhibitors

Cited by 22 publications

References 37 publications

Heat Shock Protein 90 Is Critical for Regulation of Phenotype and Functional Activity of Human T Lymphocytes and NK Cells

Heat Shock Protein 90 Is Critical for Regulation of Phenotype and Functional Activity of Human T Lymphocytes and NK Cells

EXPOSURE TO 2.45 GHz MICROWAVE RADIATION PROVOKES CEREBRAL CHANGES IN INDUCTION OF HSP-90 Î±/Î² HEAT SHOCK PROTEIN IN RAT.

Expression of heat-shock protein-90 in non-Hodgkin's lymphomas

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