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首页> 外文期刊>Journal of Cellular Physiology >The MIP‐1α autocrine loop contributes to decreased sensitivity to anticancer drugs
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The MIP‐1α autocrine loop contributes to decreased sensitivity to anticancer drugs

机译：MIP检测1α自分泌循环有助于减少对抗癌药物的敏感性

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Several autocrine soluble factors, including macrophage inflammatory protein‐1α (MIP‐1α), tumor necrosis factor‐α, and hepatocyte growth factor, promote cell survival and growth in multiple myeloma (MM) cells. We hypothesized that inhibition of the MIP‐1α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, an MIP‐1α neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of melphalan or bortezomib on MM cells. In addition, melphalan resistance cells (RPMI8226/L‐PAM and HS‐sultan/L‐PAM cells) secreted MIP‐1α and neutralizing antibody of MIP‐1α partially overcame melphalan resistance. Moreover, combination treatment with MIP‐1α neutralizing antibody and melphalan or bortezomib inhibited extracellular signal regulated kinase 1/2 (ERK1/2), Akt, and mammalian target of rapamycin (mTOR) activation, Bcl‐2, Bcl‐xL, and Survivin expression, and upregulated the expression of Bim and cleaved Poly (ADP‐ribose) polymerase (PARP). Treatment of IM9 cells with MIP‐1α siRNA suppressed the activation of ERK1/2, Akt, and mTOR, and enhanced the cytotoxic effect of melphalan and bortezomib. These results indicate that MIP‐1α neutralizing antibodies or MIP‐1α siRNA enhance the cytotoxic effect of melphalan and bortezomib by suppressing the chemokine receptor/ERK and chemokine receptor/Akt/mTOR pathways. The inhibition of MIP‐1α may thus provide a new therapeutic approach to control tumor progression and bone destruction in patients with MM.
机译：几个自分泌可溶性因子,包括巨噬细胞炎性蛋白量1α(MIP量1α),肿瘤坏死因子α应承担和肝细胞生长因素,促进细胞生存和增长多发性骨髓瘤(MM)的细胞。抑制MIP检测1α自分泌环提高抗癌药物的细胞毒性效应在MM细胞系。中和抗体抑制细胞扩散和增强细胞毒性效应美法仑或bortezomib MM细胞。此外,美法仑抵抗细胞分泌MIP 1α和中和抗体MIP 1α应承担的部分克服了美法仑阻力。此外,联合治疗与MIP 1α中和抗体,美法仑或bortezomib抑制细胞外信号调节激酶一种蛋白激酶1/2 (ERK1/2),哺乳动物的目标生存素表达和调节的表达Bim和裂解聚ADP核糖)应承担的聚合酶(PARP)。MIP小干扰rna抑制ERK1/2的激活量1α,一种蛋白激酶,mTOR和增强细胞毒性效应美法仑和bortezomib。表明MIP 1α中和抗体或应承担的MIP 1αsiRNA增强细胞毒性的影响美法仑和bortezomib通过抑制趋化因子受体/ ERK和趋化因子受体/ Akt mTOR通路。MIP 1α可能提供一个新的治疗方法来控制肿瘤进展和骨头破坏MM患者。

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