Paclitaxel-resistant cancer cell-derived secretomes elicit ABCB1-associated docetaxel cross-resistance and escape from apoptosis through FOXO3a-driven glycolytic regulation.
Paclitaxel-resistant cancer cell-derived secretomes elicit ABCB1-associated docetaxel cross-resistance and escape from apoptosis through FOXO3a-driven glycolytic regulation.
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DOI：
10.1038/emm.2016.131
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发表时间：
2017-01-20
影响因子：
12.8
通讯作者：
Lee SK
中科院分区：
文献类型：
--
作者：
Aldonza MB;Hong JY;Lee SK
化疗诱导的癌细胞分泌物促进耐药性，部分原因是糖酵解能量代谢占主导地位，这推动了癌细胞的侵袭性增殖。然而，这些分泌体的特征以及与获得性耐药相关的分子事件仍然知之甚少。在这项研究中，我们发现具有高水平紫杉醇耐药的癌细胞的分泌体促进了细胞的增殖，并抑制了药物诱导的药物敏感细胞的凋亡。我们还发现，药物(多西紫杉醇)诱导的药物敏感细胞中干扰素-α(干扰素-α)、干扰素-λ和肿瘤坏死因子-α(肿瘤坏死因子-α)的释放被这些分泌体抑制。紫杉醇耐药(PACR)癌细胞分泌体对细胞增殖的促进作用部分与细胞周期的S期增加和支持逃避凋亡的细胞死亡途径下调有关。此外，我们还发现，PACR癌细胞中靶向糖酵解的调节改变了分泌体对细胞生长、凋亡、ATP生成和获得性耐药的影响。进一步的研究表明，FOXO3a转录缺失通过挽救TRAIL的表达而加剧糖酵解转变诱导的细胞凋亡。通过建立多西紫杉醇交叉耐药的PACR癌细胞系(PACR/DCT)，我们进一步阐明了FOXO3a在糖酵解相关的P-糖蛋白/ABCB1高活性调节中的作用，从而诱导多西紫杉醇交叉耐药。这些发现表明，通过靶向糖酵解抑制细胞能量供应可能会抑制获得性化疗耐药的多样性。因此，FOXO3a的治疗抑制可能直接通过糖酵解诱导癌细胞的凋亡和克服多药耐药。
Chemotherapy-induced cancer cell secretomes promote resistance due, in part, to a predominant glycolytic energy metabolism, which drives aggressive cancer cell proliferation. However, the characterization of these secretomes and the molecular events that associate them with acquired drug resistance remain poorly understood. In this study, we show that secretomes of cancer cells with high-level paclitaxel resistance stimulated cell proliferation and suppressed drug-induced apoptosis of drug-sensitive cells. We also found that drug (docetaxel)-stimulated induction of interferon-α (IFN-α), IFN-λ and tumor necrosis factor-α (TNF-α) release in drug-sensitive cells was lowered by these secretomes. The promotion of cell proliferation by paclitaxel-resistant (PacR) cancer cell secretomes was associated, in part, with an increase in S phase of the cell cycle and downregulation of the cell death pathway that supports escape from apoptosis. In addition, we also found that the regulation of targeted glycolysis in PacR cancer cells alters the effects of the secretomes on cell growth, apoptosis, ATP generation and acquired drug resistance. Further study revealed that the deletion of FOXO3a transcription exacerbates glycolytic shift-induced apoptosis by rescuing TRAIL expression. By generating a docetaxel–cross-resistant PacR cancer cell line (PacR/DCT), we further clarified the role of FOXO3a in glycolysis-associated mediation of P-glycoprotein/ABCB1 hyperactivity that induces docetaxel cross-resistance. These findings suggest that suppression of the cellular energy supply by targeting glycolysis may inhibit the multiplicity of acquired chemotherapy resistance. Therefore, the therapeutic inhibition of FOXO3a might direct glycolysis to induce apoptosis and overcome multidrug resistance in cancer cells.