Abstract
In classical Hodgkin lymphoma (cHL) chemotherapeutic regimens are associated with stagnant rates of secondary malignancies requiring the development of new therapeutic strategies. We and others have shown that permanently activated Signal Transducer and Activator of Transcription (STAT) molecules are essential for cHL cells. Recently an overexpression of heat-shock protein 90 (HSP90) in cHL cells has been shown and inhibition of HSP90 seems to affect cHL cell survival. Here we analysed the effects of HSP90 inhibition by geldanamycin derivative 17-AAG or RNA interference (RNAi) on aberrant Jak-STAT signaling in cHL cells. Treatment of cHL cell lines with 17-AAG led to reduced cell proliferation and a complete inhibition of STAT1, -3, -5 and -6 tyrosine phosphorylation probably as a result of reduced protein expression of Janus kinases (Jaks). RNAi-mediated inhibition of HSP90 showed similar effects on Jak-STAT signaling in L428 cHL cells. These results suggest a central role of HSP90 in permanently activated Jak-STAT signaling in cHL cells. Therapeutics targeting HSP90 may be a promising strategy in cHL and other cancer entities associated with deregulated Jak-STAT pathway activation.
Highlights
Classical Hodgkin lymphoma is one of the most frequent lymphoid tumours predominantly derived from germinal centre B cells
Permanent activation of Signal Transducer and Activator of Transcription (STAT) molecules is essential in a number of malignancies regulating cell proliferation, apoptosis, immune escape and tumor angiogenesis
STAT3 and STAT6 but probably STAT5 seem to be associated with cell proliferation in Classical Hodgkin lymphoma (cHL) cell lines of B and T cell origin [1,2]
Summary
Classical Hodgkin lymphoma (cHL) is one of the most frequent lymphoid tumours predominantly derived from germinal centre B cells. We analysed the effects of the HSP90inhibitor 17-AAG as well as RNA-interference mediated inhibition of HSP90 on the tyrosine phosphorylation of STAT1, STAT3, STAT5, STAT6 and protein expression of Jak1, Jak2, Jak3 and Tyk2 in cHL cells. Due to the potential chaperone functions of HSP90, we examined the effects of 17AAG on protein amount of Jak1, Jak2, Jak3 and Tyk2 in cHL cells compared to DMSO treated cells (Figure 2C).
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