A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance

• Published in: Blood Vol. 124; no. 13; pp. 2061 - 2071
• Main Authors: Liu, Zhiqiang, Xu, Jingda, He, Jin, Zheng, Yuhuan, Li, Haiyan, Lu, Yong, Qian, Jianfei, Lin, Pei, Weber, Donna M., Yang, Jing, Yi, Qing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.09.2014; American Society of Hematology
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - genetics; Autocrine Communication; Biopsy; Bone Marrow - metabolism; Bone Marrow - pathology; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Cell Survival - genetics; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Female; Gene Expression; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Lymphoid Neoplasia; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - mortality; Multiple Myeloma - pathology; Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction; Syndecan-1 - metabolism; Trans-Activators - metabolism; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-03-557298

Hedgehog (Hh) signaling plays an important role in the oncogenesis of B-cell malignancies such as multiple myeloma (MM). However, the source of Hh ligand sonic hedgehog (SHH) and its target cells remains controversial. Previous studies showed that stromally induced Hh signaling is essential for the tumor cells and that CD19+CD138– MM stem cells are the target cells of Hh signaling. Here we demonstrate that SHH was mainly secreted by human myeloma cells but not by stromal cells in MM bone marrow. Autocrine SHH enhanced CD138+ myeloma cell proliferation and protected myeloma cells from spontaneous and stress-induced apoptosis. More importantly, autocrine SHH protected myeloma cells against chemotherapy-induced apoptosis in vitro and in vivo. Combinational treatment with chemotherapy and SHH-neutralizing antibody displayed synergistic antimyeloma effects. Mechanistic studies showed that SHH signaling activated the SHH/GLI1/BCL-2 axis, leading to the inhibition of myeloma cell apoptosis. Thus, this study identifies the myeloma autocrine Hh signaling pathway as a potential target for the treatment of MM. Targeting this pathway may improve the efficacy of chemotherapy in MM patients. •CD138+ MM cells are a major source of SHH.•Autocrine SHH enhances MM drug resistance.