Lee Sooyeun, Jang Won-Jun, Choi Boyeon, Joo Sang Hoon, Jeong Chul-Ho
College of Pharmacy, Keimyung University, Dalseo, Daegu 42601, Republic of Korea.
Department of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk 38430, Republic of Korea.
Oncol Lett. 2017 May;13(5):3437-3444. doi: 10.3892/ol.2017.5940. Epub 2017 Mar 28.
Pancreatic cancer is one of the most lethal types of cancer, due to difficulty in early detection and the limited efficacy of available treatments. Erlotinib is used to inhibit the epidermal growth factor receptor for the treatment of pancreatic cancer; however, erlotinib resistance is a major issue and the mechanisms underlying the development of erlotinib resistance remain unclear. To better understand the alterations in tumor metabolism by acquired resistance to erlotinib, an erlotinib-resistant pancreatic cancer cell line (HPAC-ER) was established, followed by a comparison of the metabolic characteristics between these cells and their erlotinib-sensitive parental cells (HPAC). This comparison was accomplished through mass spectrometry-based targeted metabolic profiling. Five metabolite groups (acylcarnitines, amino acids and biogenic amines, glycerophospholipids, sphingolipids and monosaccharides) were semi-quantified and compared statistically. These results revealed significant differences between the two groups of cells. A significant increase in the level of short-chain acylcarnitines and selected lysophosphatidylcholines, and a significant decrease in the level of acyl-alkyl-phosphatidylcholines and one sphingolipid, were observed in the HPAC-ER cells compared with the HPAC cells. The metabolic changes observed in the present study support the theory that there are increased metabolic demands in erlotinib-resistant cancer, reflecting the changes in acetyl-CoA-associated and choline phospholipid metabolism. These findings will aid in elucidating the changes that occur in pancreatic cancer metabolism through the acquired resistance to erlotinib, and in the identification of biomarkers for the early detection of pancreatic cancer.
胰腺癌是最致命的癌症类型之一，原因在于早期检测困难且现有治疗方法疗效有限。厄洛替尼用于抑制表皮生长因子受体以治疗胰腺癌；然而，厄洛替尼耐药是一个主要问题，其耐药发生的机制仍不清楚。为了更好地了解获得性厄洛替尼耐药对肿瘤代谢的改变，建立了一种厄洛替尼耐药的胰腺癌细胞系（HPAC-ER），随后比较这些细胞与其厄洛替尼敏感的亲本细胞（HPAC）之间的代谢特征。这种比较是通过基于质谱的靶向代谢谱分析完成的。对五个代谢物组（酰基肉碱、氨基酸和生物胺、甘油磷脂、鞘脂和单糖）进行了半定量并进行统计学比较。这些结果揭示了两组细胞之间的显著差异。与HPAC细胞相比，在HPAC-ER细胞中观察到短链酰基肉碱和选定的溶血磷脂酰胆碱水平显著升高，而酰基烷基磷脂酰胆碱和一种鞘脂水平显著降低。本研究中观察到的代谢变化支持了以下理论，即厄洛替尼耐药的癌症中代谢需求增加，反映了与乙酰辅酶A相关的代谢变化以及胆碱磷脂代谢的变化。这些发现将有助于阐明胰腺癌代谢通过获得性厄洛替尼耐药所发生的变化，并有助于识别用于胰腺癌早期检测的生物标志物。
