HSP90 is a key for telomerase activation and malignant transition in pheochromocytoma

Recent studies on a limited number of pheochromocytomas (PCs) revealed a potential role of telomerase in the malignant transition of these tumors. Telomerase is a ribonucleoprotein complex that includes the telomerase RNA component (hTR), the telomerase-associated protein (TP1), the telomerase catalytic subunit (hTERT), and the heat-shock protein 90 (HSP90). The interactions between these subunits and the activation machinery of telomerase are still unclear. To test whether the expression and regulation of telomerase subunits are reflected in the malignant transition of PCs, we determined their mRNA and/or protein expression in 28 benign and 9 malignant PCs and compared the results with telomerase activity. Reverse transcriptase polymerase chain reaction analysis revealed that TP1 was ubiquitously expressed. hTR was found in all malignant (100%) and in 13/28 (46%) benign PCs. By contrast, hTERT was clearly associated with aggressive biologic behavior. All the malignant (100%) but only 2/28 benign (7%) PCs expressed hTERT. HSP90 was increased in malignant PCs but was also expressed at a lower level in benign tumors. High telomerase activity was measurable in only hTERT-positive tissues. Our data indicate that hTERT, HSP90, and telomerase activity are upregulated in malignant cells of the adrenal medulla. Overexpression of HSP90 is an important factor in the activation of telomerase via hTERT. The common expression of hTERT and telomerase activity thus represents an additional prognostic marker that may identify more aggressive tumors.