Department of Gastroenterology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Jingzhou Street 39, Xiangyang 441021, China.
Department of Gastroenterology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Jingzhou Street 39, Xiangyang 441021, China.
Clin Res Hepatol Gastroenterol. 2021 Jan;45(1):101456. doi: 10.1016/j.clinre.2020.04.020. Epub 2020 Jun 5.
The clinical management of gastric cancer still remains challenge due to its poor response to chemotherapy. Better understanding the underlying mechanisms is required for the identification of more comprehensive therapies to overcome chemoresistance in gastric cancer.
GBA1 level was systematically analyzed in gastric cancer patients before and after chemotherapy, and gastric cancer cells exposed to long-term chemo agent's treatment. The roles of GBA1 and its downstream mechanisms were investigated using pharmacological and genetic approaches.
We observed the time-dependent upregulation of GBA1 expression and enzyme activity in multiple gastric cancer cell lines in response to prolonged exposure of 5-FU. It is noted that this phenomenon was also observed in gastric cancer patients after chemotherapy. Interestingly, no significant differences on GBA1 expression were detected between normal and malignant gastric tissues. These suggest that the predominant role of GBA1 is in the development of gastric cancer chemoresistance rather than tumorigenesis. Functional analysis demonstrated that GBA1 inhibition suppressed gastric cancer growth and survival without affecting migration, and augmented 5-FU's efficacy. Consistently, GBA1 inhibition was active against 5-FU-resistant gastric cancer cells. Mechanism studies showed that GBA1 inhibition led to loss of lysosomal integrity and function in 5-FU-resistant gastric cancer cells.
We are the first to show that inhibition of β-glucosidase (encoded by GBA1) sensitizes gastric cancer to chemotherapy. Our findings demonstrate the therapeutic value of inhibiting GBA1 in gastric cancer, particularly in those who develop chemoresistance.
由于胃癌对化疗的反应不佳，其临床治疗仍然具有挑战性。需要更好地了解潜在机制，以确定更全面的治疗方法来克服胃癌的化疗耐药性。
系统分析了化疗前后胃癌患者和长期接受化疗药物治疗的胃癌细胞中的 GBA1 水平。使用药理学和遗传学方法研究了 GBA1 及其下游机制的作用。
我们观察到，在多种胃癌细胞系中，5-FU 长时间暴露后，GBA1 的表达和酶活性呈时间依赖性上调。值得注意的是，这一现象也在化疗后的胃癌患者中观察到。有趣的是，正常和恶性胃组织之间 GBA1 表达没有明显差异。这表明 GBA1 的主要作用是在胃癌的化疗耐药性发展中，而不是在肿瘤发生中。功能分析表明，GBA1 抑制抑制了胃癌的生长和存活，而不影响迁移，并增强了 5-FU 的疗效。一致地，GBA1 抑制对 5-FU 耐药的胃癌细胞有效。机制研究表明，GBA1 抑制导致 5-FU 耐药的胃癌细胞溶酶体完整性和功能丧失。
我们是第一个表明抑制β-葡萄糖苷酶（由 GBA1 编码）可使胃癌对化疗敏感的人。我们的研究结果表明，抑制 GBA1 在胃癌中的治疗价值，特别是在那些发生化疗耐药的患者中。
