Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

Abstract

Purpose: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.Experimental Design: Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.Results: Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R-signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.Conclusions: We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials.

Cytoplasm estrogen receptor β5 as an improved prognostic factor in thymoma and thymic carcinoma progression

“…In addition, the present study indicated that high cERβ5 expression in thymic tumors was correlated with longer OS and PFS, which was in accordance with previous results (18,20,21,23,28,29). However, the fact that cERβ5 was overexpressed in thymic tumors, while having an inhibiting biological effect, suggested that cERβ5 may be involved in other functions of the thymic tumor development and progression.…”

“…Exposure to sex steroid hormones, for instance during estrogen therapy, results in thymic atrophy and loss of cellularity in animals (18,20,21). Thymic atrophy induced by estrogens contributes towards certain complicated and unclear mechanisms.…”

“…The thymic carcinoma cell line, TC1889, and the thymoma cell line, T1682, were established, characterized and verified as previously described (18).…”

PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

“…As described in other cancer types [83,[124][125][126], PU-H71 also potentiated G 2 /M arrest, and depleted Hsp90 client proteins AKT, pERK, RAF-1, c-MYC, c-KIT, IGF1R, hTERT (human telomerase reverse transcriptase) and EWS-FLI1 (Ewing's sarcoma-Friend leukemia integration 1 transcription factor). In regards to potential drug synergy with bortezomib, Fa-CI (fraction affected-combination index) plots and isobolographic analyses confirmed synergism between PU-H71 and bortezomib.…”

Molecular aspects of thymic carcinoma

“…IGF-1R protein overexpression has also been observed in thymic carcinoma, being present in 6 of 7 thymic carcinomas in a study by Girard et al [16]. Using thymic carcinoma cell lines these results were confirmed by Breinig et al [37]. In addition, the authors were able to demonstrate that heat shock protein 90 (Hsp90) inhibition was associated with antitumor activity by blocking multiple cancer-relevant signaling pathways, including the IGF-1R pathway.…”