Salaroglio Iris Chiara, Campia Ivana, Kopecka Joanna, Gazzano Elena, Orecchia Sara, Ghigo Dario, Riganti Chiara
Department of Oncology, University of Torino, Italy.
S.C. Anatomia Patologica, Azienda Ospedaliera S.S. Antonio e Biagio, Alessandria, Italy.
Oncotarget. 2015 Jan 20;6(2):1128-42. doi: 10.18632/oncotarget.2731.
The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.
人类恶性间皮瘤（HMM）具有化学抗性和免疫抑制表型。目前缺乏恢复对HMM化学敏感性和免疫反应性的有效策略。我们研究了使用唑来膦酸是否是一种有效的化学免疫致敏策略。我们将原发性HMM样本与未转化的间皮细胞进行了比较。HMM细胞具有更高的胆固醇和类异戊二烯合成率、Ras/细胞外信号调节激酶1/2（ERK1/2）/缺氧诱导因子-1α（HIF-1α）途径的组成性激活以及药物外排转运蛋白P-糖蛋白（Pgp）的上调。通过减少类异戊二烯供应，唑来膦酸下调了Ras/ERK1/2/HIF-1α/Pgp轴，并使HMM细胞对Pgp底物产生化学敏感性。HMM细胞还产生了更高量的犬尿氨酸，降低了T淋巴细胞的增殖，并增加了调节性T（Treg）细胞的数量。犬尿氨酸的合成是由于吲哚胺2,3-双加氧酶（IDO）的转录，这是信号转导和转录激活因子-3（STAT3）激活的结果。通过降低Ras/ERK1/2/STAT3/IDO轴的活性，唑来膦酸降低了犬尿氨酸的合成和Treg细胞的扩增，并增加了T淋巴细胞的增殖。由于唑来膦酸能够降低Ras/ERK1/2活性，而Ras/ERK1/2活性既导致Pgp介导的化学抗性又导致IDO介导的免疫抑制，因此唑来膦酸是HMM细胞中一种有效的化学免疫致敏剂。
