Expression of heat‐shock proteins hsp27, hsp70 and hsp90 in malignant epithelial tumour of the ovaries

Elpek, Gülsüm Özlem; Karaveli, Şeyda; Şimşek, Tayyup; Keles, Nuran; Aksoy, Nazif Hikmet

doi:10.1034/j.1600-0463.2003.1110411.x

Cited by 64 publications

(57 citation statements)

References 25 publications

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“…Because increased stage is a harbinger of worse outcome, this would suggest that Hsp27 may be a marker of better survival. Our findings are opposite to the trend previously published which associated the presence of Hsp27 with poor survival of ovarian cancer patients (38). Our findings were done in a background wherein survival could not be ascertained, and the second study did not reach statistical significance for the poor outcome finding.…”

Section: Discussioncontrasting

confidence: 57%

“…Hsp70 can protect cancer cells from death after stresses, such as heat shock and chemotherapy (38,39), and has been proposed to cause resistance of ovarian cancer cells to farnesyltransferase inhibitors (4). Hsp70 is known to shuttle between the cytoplasm and the nucleus and remains in the nucleus during times of cellular stress to protect cells from death (40).…”

Section: Discussionmentioning

confidence: 99%

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BAG-4/SODD and Associated Antiapoptotic Proteins Are Linked to Aggressiveness of Epithelial Ovarian Cancer

Annunziata¹,

Kleinberg

Davidson

et al. 2007

Clinical Cancer Research

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Purpose: We hypothesized that elevated expression in ovarian cancer of the BAG family of prosurvival proteins and associated partners would be associated with clinical features of aggressiveness in ovarian cancer. Experimental Design: Expression patterns of BAG-1, BAG-3, BAG-4, and Bcl-xL were determined by immunohistochemical analysis of tissue samples obtained at diagnosis from 28 women with stage III or stage IV ovarian cancer treated with cisplatin, paclitaxel, and cyclophosphamide after initial cytoreduction. Association of these proteins, BAG-6, heat shock protein 70 (Hsp70), Hsp27, and Bcl-2, with clinical variables was tested in ovarian cancer tissue arrays from Gynecologic Oncology Group tissue bank. Results: A statistically significant relationship was found between elevated cytoplasmic expression of BAG-4 and improved overall (P = 0.0002) and progression-free survival (P = 0.003) in the prospectively collected samples. Bcl-2 staining was significantly more frequent on the tissue array in lower stage (P = 0.005) and grade (P = 0.0009) tumors, whereas Hsp70 was prominent in higher grade cases (P = 0.002). Furthermore, Bcl-xL was more closely associated with serous compared with endometrioid ovarian cancers (P = 0.004). Conclusion: Unexpectedly, cytoplasmic expression of BAG-4 and Bcl-2 marked less aggressive ovarian cancer, whereas nuclear Hsp70 suggested more aggressive behavior. Bcl-xL may play a more prominent function in the pathology of serous histology ovarian cancers compared with the endometrioid subtype. The findings presented here support involvement of these proteins in the propagation of ovarian cancer and provide a basis for the development of molecular therapeutics modulating these survival pathways.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

BAG-4/SODD and Associated Antiapoptotic Proteins Are Linked to Aggressiveness of Epithelial Ovarian Cancer

Annunziata¹,

Kleinberg

Davidson

et al. 2007

Clinical Cancer Research

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“…Increased expression of Hsp90 was observed in cutaneous melanoma, breast tumors, lung cancer, leukemias, and Hodgkin's disease (5,13,22,23) and has been shown to correlate with an increase in malignant phenotype in breast cancer (24) and gastric cancer (25). Conversely, the expression of Hsp90 is associated with good prognosis in endometrial cancer (26), whereas expression of Hsp90 was seen to be of no prognostic significance in ovarian cancer (27) and salivary gland tumors (28).…”

Section: Discussionmentioning

confidence: 99%

Immune Expression and Inhibition of Heat Shock Protein 90 in Uveal Melanoma

Faingold

Marshall

Antecka

et al. 2008

Clinical Cancer Research

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Purpose:To examine the immunohistochemical profile of heat shock protein 90 (Hsp90) in uveal melanoma and the cytotoxicity of an Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), in uveal melanoma cell lines. Experimental Design: Hsp90 expression was determined by immunohistochemistry in 44 paraffin-embedded sections of primary human uveal melanoma and in five uveal melanoma cell lines (92.1, OCM-1, MKT-BR, SP6.5, and UW-1). Sulforhodamine B^based proliferation assay was used to compare uveal melanoma cell growth with a range of concentrations of 17-AAG. Changes in cell migration, invasion, cell cycle fractions, and apoptotic activity were also evaluated. Expression of intracellular proteins was determined by Western blot analysis after 17-AAG exposure.Results: Immunohistochemical expression of Hsp90 was identified in 68% of the paraffinembedded sections and significantly associated with largest tumor dimension (P = 0.03). 17-AAG significantly reduced the proliferation rates of uveal melanoma cell lines, with concentrations of 100 to 0.1 Amol/L. 17-AAG also significantly reduced the migratory and invasive capabilities of uveal melanoma cell lines. Cell cycle analysis showed that 17-AAG induced accumulations of cells in G 1 . Caspase-3 protease activity analysis, a marker for apoptosis, showed a significant increase after drug exposure. The cytotoxic effect of 17-AAG was associated with decreased levels of phosphorylated Akt and cyclin-dependent kinase 4. Conclusions: The immunohistochemical expression of Hsp90 in uveal melanoma indicates worse prognosis.To the best of our knowledge, this is the first report showing the inhibitory effect on uveal melanoma cells using 17-AAG to target Hsp90. Therefore, Hsp90 may be used as a potential target for treatment of patients with uveal melanoma.

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“…15 Hsp90 in particular is highly expressed in ovarian cancer, and its expression correlates with FIGO stage. 16,17 Moreover, mounting evidence links Hsp90 with cancer cell migration, and myosin II and Hsp90 inhibitors show promise for cancer treatment. 18 -22 There are two UCS orthologs expressed in mammalian cells: SM UNC-45 (striated muscle UNC-45) whose expression is restricted to skeletal muscle and heart, and GC UNC-45 (general cell UNC-45 comprising 20 exons of chromosome 15), which is expressed in several organs including ovaries where GC mRNA levels are particularly abundant.…”

mentioning

confidence: 99%

Myosin II Co-Chaperone General Cell UNC-45 Overexpression Is Associated with Ovarian Cancer, Rapid Proliferation, and Motility

Bazzaro¹,

Santillan²,

Lin

et al. 2007

The American Journal of Pathology

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Both tumor cell proliferation and metastasis are dependent on myosin II. Because UNC-45 is required to chaperone the assembly of a functional myosin II motor, we examined the expression of the general cell (GC) UNC-45 isoform in ovarian tumors. Serous carcinoma expressed elevated levels of GC UNC-45 compared with normal ovarian surface epithelium and benign cystadenoma. High-stage exhibited greater GC UNC-45 expression than low-stage serous carcinoma. Similarly, GC UNC-45 transcripts and protein levels were higher in ovarian cell lines than in immortalized ovarian surface epithelial cells. Elevation of GC UNC-45 levels by ectopic expression enhanced the rate of ovarian cancer cell proliferation, whereas siRNA knockdown of GC UNC-45 suppressed proliferation without altering myosin II levels. GC UNC-45 and myosin II were diffuse within the cytoplasm of confluent interphase cells, but both accumulated together at the cleavage furrow during cytokinesis. GC UNC-45 and myosin II also trafficked to the leading edges of ovarian cancer cells induced to move in a scratch assay. Knockdown of GC UNC-45 reduced the spreading ability of ovarian cancer cells whereas it was enhanced by GC UNC-45 overexpression. In sum, these findings implicate elevated GC UNC-45 protein expression in ovarian carcinoma proliferation and metastasis. Epithelial ovarian cancer is the most lethal gynecological malignancy and the fifth major cause of cancer death among women in the United States. Approximately 70% of ovarian cancer patients are diagnosed with disease that has spread beyond the ovaries when, despite aggressive surgery and chemotherapy, the 5-year survival rate is less than 30%. Ovarian carcinoma rapidly seeds the peritoneal cavity with highly proliferative and invasive cancer cells, and new therapies targeting both of these properties are urgently needed.

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Expression of heat‐shock proteins hsp27, hsp70 and hsp90 in malignant epithelial tumour of the ovaries

Cited by 64 publications

References 25 publications

BAG-4/SODD and Associated Antiapoptotic Proteins Are Linked to Aggressiveness of Epithelial Ovarian Cancer

BAG-4/SODD and Associated Antiapoptotic Proteins Are Linked to Aggressiveness of Epithelial Ovarian Cancer

Immune Expression and Inhibition of Heat Shock Protein 90 in Uveal Melanoma

Myosin II Co-Chaperone General Cell UNC-45 Overexpression Is Associated with Ovarian Cancer, Rapid Proliferation, and Motility

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