Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
Key Laboratory of Hematological Disease Diagnostic and Treat Centre of Guizhou Province, Guiyang 550004, China.
Aging (Albany NY). 2020 Apr 16;12(8):6611-6629. doi: 10.18632/aging.102996.
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.
化疗耐药性仍然是硼替佐米为基础的化疗治疗多发性骨髓瘤（MM）的一个关键挑战。最近的研究表明，血红素加氧酶-1（HO-1）参与了癌细胞的凋亡、增殖和耐药性。本研究旨在探讨 HO-1 在硼替佐米对骨髓瘤细胞敏感性中的作用和机制。在研究人群中，我们发现 HO-1 在 CD138 原发性骨髓瘤细胞中高度表达，与 MM 患者的 Gas6 表达和 Gas6 血浆水平呈正相关。使用药理学抑制剂 ZnPPIX 或 siRNA 敲低下调 HO-1，可显著增强人原发性 CD138 细胞、U266 和 RPMI8226 细胞系中硼替佐米对骨髓瘤细胞的敏感性。在机制上，HO-1 通过 ERK/STAT3 轴调节 Gas6 的产生。与 HO-1 抑制联合使用可通过抑制 Gas6 的产生，增加硼替佐米诱导的细胞凋亡和抗增殖作用。这些发现表明，硼替佐米和 HO-1 抑制剂的联合应用可能成为治疗硼替佐米耐药性 MM 的有前途的治疗靶点。
