Heme oxygenase-1 inhibition mediates Gas6 to enhance bortezomib-sensitivity in multiple myeloma via ERK/STAT3 axis
| Autor: | Xingyi Kuang, Jie Xiong, Jishi Wang, Dan Ma, Qin Fang, Zhaoyuan Zhang, Weili Wang, Siyu Zhang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Adult Male STAT3 Transcription Factor Aging MAP Kinase Signaling System Protoporphyrins Antineoplastic Agents Apoptosis Bortezomib Downregulation and upregulation immune system diseases hemic and lymphatic diseases Cell Line Tumor Gas6 medicine Humans RNA Messenger Enzyme Inhibitors RNA Small Interfering bortezomib-sensitivity Multiple myeloma Aged Aged 80 and over Chemistry heme oxygenase-1 Cell Biology Middle Aged medicine.disease Antibodies Neutralizing Heme oxygenase multiple myeloma ERK/STAT3 axis Cell culture Drug Resistance Neoplasm Gene Knockdown Techniques Cancer cell Cancer research Intercellular Signaling Peptides and Proteins Female Syndecan-1 medicine.drug Research Paper |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| Popis: | Chemoresistance is still a critical challenge for efficient treatment of multiple myeloma (MM) during the bortezomib-based chemotherapy. Recent studies have suggested that heme oxygenase-1 (HO-1) is involved in apoptosis, proliferation and chemoresistance in cancer cells. Here we aim to investigate the role and mechanism of HO-1 in bortezomib-sensitivity to myeloma cells. In the study population, we found that HO-1 was highly expressed in CD138+ primary myeloma cells, which was positively associated with Gas6 expression and Gas6 plasma levels in MM patients. Downregulation of HO-1 using pharmacological inhibitor ZnPPIX or siRNA knockdown significantly enhanced myeloma cell sensitivity to bortezomib in human primary CD138+ cells, U266 and RPMI8226 cell lines. Mechanistically, HO-1 regulated Gas6 production via ERK/STAT3 axis. Combination with HO-1 inhibition increased bortezomib-induced apoptosis and antiproliferative effects via suppressing Gas6 production. These findings suggest that combination of bortezomib and HO-1 inhibitor may serve as a promising therapeutic target against bortezomib-resistant MM. |
| Databáze: | OpenAIRE |
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