Content area
Full text
Introduction
Osteosarcoma (OS) is the most common type of primary malignant bone tumor and it primarily affects children and adolescents (1). The outcome of patients with OS may improve through a combination of surgery and chemotherapy, and the 5-year survival rate has increased to 60–70% over the past 30 years (2,3). However, a considerable number of patients are either not sensitive to chemotherapy or develop drug resistance to the currently available chemotherapeutic regimens (4). Therefore, it is crucial to elucidate the mechanisms underlying the development of chemoresistance in these patients and to develop new strategies for the treatment of OS.
Numerous studies have demonstrated that cancer stem cells (CSCs) are not only the cause of relapse and metastasis, but also contribute to chemoresistance in tumors (5–8). OS stem cells (OSCs) have recently been identified as a subset of CSCs using a distinct set of stem cell markers, including CD133, aldehyde dehydrogenase 1 (ALDH1), CD117/Stro-1 and CD271 (9–12). Additional stem cell markers, such as octamer-binding transcription factor 4 (Oct-4), sex determining region Y-box 2 (Sox 2) and Nanog, have also been recommended for distinguishing OSC populations from other cells (13–15). OS sarcosphere cells exhibit CSC characteristics and display high expression levels of markers associated with stem cell self-renewal, tumorigenicity, and multiple drug resistance (16).
The heat shock protein (Hsp)90 inhibitor, 17-AAG (tanespimycin), interferes with the binding of ATP to Hsp90 and results in the proteasome-mediated degradation of Hsp90 client protein complexes (17,18). 17-AAG significantly enhances the cytotoxicity of etoposide in human colon cancer HCT116 cells (19). As known Hsp90 client proteins are required for the maintenance of self-renewal, this requirement for self-renewal may be exploited by treatment with 17-AAG. Indeed, several studies have demonstrated that 17-AAG can effectively target CSCs (20,21). However, little is known on the effects of 17-AAG on OSCs, and the molecular mechanisms underlying its antitumor activity remain to be determined.
The Hedgehog signaling pathway plays a key role in the development of several CSCs, such as glioblastoma stem cells, CD34+ leukemic cells and gastric CSCs (22–24). The Hedgehog signaling pathway is primarily dependent on the Gli transcription factor family (Gli1-3), which are its downstream effectors. Specifically, Gli1 is the principal transcriptional effector that regulates gene expression in response to Hedgehog...