吉西他滨耐药胰腺癌细胞的蛋白质组学分析显示，微管相关蛋白2上调与紫杉烷治疗相关。
Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment.
作者信息
Le Large Tessa Ya Sung, El Hassouni Btissame, Funel Niccola, Kok Bart, Piersma Sander R, Pham Thang V, Olive Kenneth P, Kazemier Geert, van Laarhoven Hanneke W M, Jimenez Connie R, Bijlsma Maarten F, Giovannetti Elisa
机构信息
Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, NetherlandsLEXOR, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, NetherlandsCancer Pharmacology Lab, AIRC-Start-Up, University Hospital of Pisa, Pisa, Italy.
Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands.
出版信息
Ther Adv Med Oncol. 2019 May 10;11:1758835919841233. doi: 10.1177/1758835919841233. eCollection 2019.
BACKGROUND
Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). Here we aimed to evaluate the (phospho)proteome of gemcitabine-sensitive and gemcitabine-resistant PDAC cells to identify novel therapeutic targets and predictive biomarkers.
METHODS
The oncogenic capabilities of gemcitabine-sensitive and resistant PDAC cells were evaluated and . Cultured cells were analyzed by label-free proteomics. Differential proteins and phosphopeptides were evaluated by gene ontology and for their predictive or prognostic biomarker potential with immunohistochemistry of tissue microarrays.
RESULTS
Gemcitabine-resistant cells had increased potential to induce xenograft tumours ( value < 0.001). Differential analyses showed that proteins associated with gemcitabine resistance are correlated with microtubule regulation. Indeed, gemcitabine-resistant cells displayed an increased sensitivity for paclitaxel ( < 0.001) and nab-paclitaxel had a strong anti-tumour efficacy . Microtubule-associated protein 2 (MAP2) was found to be highly upregulated ( = 0.002, fold change = 10) and phosphorylated in these resistant cells. Expression of MAP2 was correlated with a poorer overall survival in patients treated with gemcitabine in the palliative ( = 0.037) and adjuvant setting ( = 0.014).
CONCLUSIONS
These data show an explanation as to why the combination of gemcitabine with nab-paclitaxel is effective in PDAC patients. The identified gemcitabine-resistance marker, MAP2, emerged as a novel prognostic marker in PDAC patients treated with gemcitabine and warrants further clinical investigation.
背景
化疗耐药阻碍了胰腺导管腺癌（PDAC）患者的治疗。在此，我们旨在评估吉西他滨敏感和耐药的PDAC细胞的（磷酸化）蛋白质组，以确定新的治疗靶点和预测性生物标志物。
方法
评估了吉西他滨敏感和耐药PDAC细胞的致癌能力。通过无标记蛋白质组学分析培养的细胞。通过基因本体论评估差异蛋白和磷酸肽，并通过组织微阵列的免疫组织化学评估其作为预测或预后生物标志物的潜力。
结果
吉西他滨耐药细胞诱导异种移植肿瘤的潜力增加（值<0.001）。差异分析表明，与吉西他滨耐药相关的蛋白质与微管调节相关。事实上，吉西他滨耐药细胞对紫杉醇的敏感性增加（<0.001），纳米白蛋白紫杉醇具有很强的抗肿瘤疗效。发现微管相关蛋白2（MAP2）在这些耐药细胞中高度上调（=0.002，倍数变化=10）并发生磷酸化。在接受姑息性（= 0.037）和辅助性（=0.014）吉西他滨治疗的患者中，MAP2的表达与较差的总生存期相关。
结论
这些数据解释了为什么吉西他滨与纳米白蛋白紫杉醇联合使用对PDAC患者有效。鉴定出的吉西他滨耐药标志物MAP2，在接受吉西他滨治疗的PDAC患者中作为一种新的预后标志物出现，值得进一步临床研究。
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