Abstract
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.
Highlights
Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by aberrant proliferation of plasma cells within the bone marrow [1]
Our main findings demonstrate that heme oxygenase-1 (HO-1) is associated with increased Gas6 expression in MM patients, and inhibition of HO-1 enhances sensitivity to bortezomib in myeloma cells via suppressing Gas6 expression and secretion
We have demonstrated that HO-1 expression levels were progressively elevated from stage I to III of MM patients
Summary
Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by aberrant proliferation of plasma cells within the bone marrow [1]. It can cause multiple organ dysfunctions such as renal insufficiency, anemia, frequent infection, hypercalcemia and bone destruction, which has become an increasing public health burden [2]. The amount of MM patients who receive bortezomib-based therapeutic regimens is more than 80%, yet most of them inevitably develop acquired resistance to bortezomib, which has been a critical challenge in clinic [5]. There is an urgent need in clinic for understanding the mechanism of bortezomib resistance and identifying the effective target against this resistance
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