Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation.
Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation.
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DOI：
10.18632/oncotarget.6020
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发表时间：
2015-10-27
期刊：
影响因子：
--
通讯作者：
Yang J
中科院分区：
文献类型：
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作者：
Liu Z;Xu J;He J;Liu H;Lin P;Wan X;Navone NM;Tong Q;Kwak LW;Orlowski RZ;Yang J
多发性骨髓瘤患者的一个主要问题是化疗耐药性，其在与骨髓基质细胞相互作用后在骨髓瘤细胞中发展。然而，很少有研究确定骨髓脂肪细胞（骨髓基质细胞的主要成分）在骨髓瘤化疗耐药性中的作用。我们发现，成熟的人脂肪细胞激活自噬和上调自噬蛋白的表达，从而抑制化疗诱导的胱天蛋白酶裂解和骨髓瘤细胞凋亡。我们发现，脂肪细胞分泌已知的和新的脂肪因子，如瘦素和adipsin。这些脂肪因子的加入增强了自噬蛋白的表达，减少了骨髓瘤细胞的凋亡。体内研究进一步证明了骨髓源性脂肪细胞在降低骨髓瘤细胞对化疗反应中的重要性。我们的研究结果表明，脂肪细胞，脂肪细胞分泌的脂肪因子和脂肪细胞激活的自噬是对抗化疗耐药性和提高骨髓瘤患者治疗效果的新靶点。
A major problem in patients with multiple myeloma is chemotherapy resistance, which develops in myeloma cells upon interaction with bone marrow stromal cells. However, few studies have determined the role of bone marrow adipocytes, a major component of stromal cells in the bone marrow, in myeloma chemotherapy resistance. We reveal that mature human adipocytes activate autophagy and upregulate the expression of autophagic proteins, thereby suppressing chemotherapy-induced caspase cleavage and apoptosis in myeloma cells. We found that adipocytes secreted known and novel adipokines, such as leptin and adipsin. The addition of these adipokines enhanced the expression of autophagic proteins and reduced apoptosis in myeloma cells. In vivo studies further demonstrated the importance of bone marrow-derived adipocytes in the reduced response of myeloma cells to chemotherapy. Our findings suggest that adipocytes, adipocyte-secreted adipokines, and adipocyte-activated autophagy are novel targets for combatting chemotherapy resistance and enhancing treatment efficacy in myeloma patients.