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Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion
Author(s) -
Yu Kunlin,
Wang Jishi,
Lu Tingting,
Ma Dan,
Wei Danna,
Guo Yongling,
Cheng Bingqin,
Wang Weili,
Fang Qin
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29046
Subject(s) - heme oxygenase , secretion , lymphoblastic leukemia , heme , cancer research , vincristine , chemistry , microbiology and biotechnology , immunology , leukemia , biology , medicine , biochemistry , enzyme , chemotherapy , cyclophosphamide
Chemoresistance often causes treatment failure of B‐cell acute lymphoblastic leukemia (B‐ALL). However, the mechanism remains unclear at present. Herein, overexpression of heme oxygenase‐1 (HO‐1) was found in the bone marrow stromal cells (BMSCs) from B‐ALL patients developing resistance to vincristine (VCR), a chemotherapeutic agent. Two B‐ALL cell lines Super B15 and CCRF‐SB were cocultured with BMSCs transfected with lentivirus to regulate the expression of HO‐1. Silencing HO‐1 expression in BMSCs increased the apoptotic rates of B‐ALL cell lines induced by VCR, whereas upregulating HO‐1 expression reduced the rate. Cell cycle can be arrested in the G2/M phase by VCR. In contrast, B‐ALL cells were arrested in the G0/G1 phase due to HO‐1 overexpression in BMSCs, which avoided damage from the G2/M phase. Vascular endothelial growth factor (VEGF) in BMSCs, as a key factor in the microenvironment‐associated chemoresistance, was also positively coexpressed with HO‐1. VEGF secretion was markedly increased in BMSCs with HO‐1 upregulation but decreased in BMSCs with HO‐1 silencing. B‐ALL cell lines became resistant to VCR when cultured with VEGF recombinant protein, so VEGF secretion induced by HO‐1 expression may promote the VCR resistance of B‐ALL cells. As to the molecular mechanism, the PI3K/AKT pathway mediated regulation of VEGF by HO‐1. In conclusion, this study clarifies a mechanism by which B‐ALL is induced to resist VCR through HO‐1 overexpression in BMSCs, and provides a novel strategy for overcoming VCR resistance in clinical practice.