Center for Clinical Mass Spectrometry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
J Zhejiang Univ Sci B. 2024 Jan 15;25(1):51-64. doi: 10.1631/jzus.B2200652.
Pancreatic cancer is among the most malignant cancers, and thus early intervention is the key to better survival outcomes. However, no methods have been derived that can reliably identify early precursors of development into malignancy. Therefore, it is urgent to discover early molecular changes during pancreatic tumorigenesis. As aberrant glycosylation is closely associated with cancer progression, numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis; however, detailed glycoproteomic information, especially site-specific -glycosylation changes in pancreatic cancer with and without drug treatment, needs to be further explored. Herein, we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans, glycosites, and intact glycopeptides in pancreatic cancer cells and patient sera. The profiling of -glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells, whereas human sera, which contain many secreted glycoproteins, had significant changes of glycans at their specific glycosites. These results indicated the potential role for tumor-specific glycosylation as disease biomarkers. We also found that AMG-510, a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog () G12C mutation, profoundly reduced the glycosylation level in MIA PaCa-2 cells, suggesting that plays a role in the cellular glycosylation process, and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.
胰腺癌是最恶性的癌症之一，因此早期干预是改善生存结果的关键。然而，目前还没有能够可靠地识别发展为恶性肿瘤的早期前体的方法。因此，迫切需要发现胰腺癌发生过程中的早期分子变化。由于异常糖基化与癌症进展密切相关，因此已经做出了许多努力来挖掘糖基化变化作为诊断的生物标志物；然而，详细的糖蛋白质组学信息，特别是有和没有药物治疗的胰腺癌中的特定糖基化位点的变化，需要进一步探索。在这里，我们使用综合固相化学酶促糖蛋白质组学分析了胰腺癌细胞和患者血清中的聚糖、糖基位点和完整糖肽。癌细胞中 -聚糖的分析表明，来自 MIA PaCa-2 细胞原发性肿瘤的分泌糖蛋白增加，而含有许多分泌糖蛋白的人血清在其特定糖基位点上的聚糖发生了显著变化。这些结果表明肿瘤特异性糖基化作为疾病生物标志物的潜在作用。我们还发现，小分子抑制剂 AMG-510 针对 Kirsten 大鼠肉瘤病毒致癌基因同源物 () G12C 突变，显著降低了 MIA PaCa-2 细胞的糖基化水平，表明在细胞糖基化过程中发挥作用，因此糖基化抑制有助于 AMG-510 的抗肿瘤作用。
