School of Bioengineering, Hangzhou Medical College, Zhejiang Province, Hangzhou, 310013, China.
Zhejiang Provincial Key Laboratory of Neuropsychiatric Drug Research, Hangzhou Medical College, Zhejiang Province, Hangzhou, 310013, China.
J Physiol Biochem. 2022 Aug;78(3):679-687. doi: 10.1007/s13105-022-00894-5. Epub 2022 Jun 8.
Conventional chemotherapy plays a key role in hepatocellular carcinoma (HCC) treatment, however, with intrinsic or acquired chemoresistance being a major constraint. Here, we aimed to identify potential target to reverse such chemoresistance. In the present study, we found significant difference in uridine monophosphate synthetase (UMPS) expression between 5-FU resistant and sensitive HCC cell lines and the overexpression or downregulation of UMPS impacted 5-FU response in HCC cells. We further found that inhibition of UMPS activity with uric acid at concentration present in human plasma decreased the 5-FU sensitivity of HCC cells, while reduction of uric acid levels with uricase improved the 5-FU sensitivity of HCC cells as well as colorectal cancer cells. In vivo studies also suggested that modulation of uric acid levels did affect 5-FU sensitivity of tumors. These data indicated that UMPS was correlated with the 5-FU resistance in HCC cells and uricase sensitized cancer cells to 5-FU through uricase-uric acid-UMP synthase axis, which provided a potential strategy to improve the efficacy of 5-FU-based chemotherapy for human cancers.
传统化疗在肝细胞癌 (HCC) 治疗中起着关键作用，然而，内在或获得性化疗耐药性是一个主要的限制。在这里，我们旨在确定潜在的靶点来逆转这种耐药性。在本研究中，我们发现尿嘧啶单磷酸合成酶 (UMPS) 在 5-FU 耐药和敏感 HCC 细胞系之间的表达存在显著差异，UMPS 的过表达或下调影响 HCC 细胞对 5-FU 的反应。我们进一步发现，尿酸在人血浆中存在的浓度抑制 UMPS 活性降低了 HCC 细胞对 5-FU 的敏感性，而尿酸酶降低尿酸水平也提高了 HCC 细胞和结直肠癌细胞对 5-FU 的敏感性。体内研究也表明，尿酸水平的调节确实影响了肿瘤对 5-FU 的敏感性。这些数据表明，UMPS 与 HCC 细胞中 5-FU 的耐药性相关，尿酸酶通过尿酸酶-尿酸-UMP 合成酶轴使癌细胞对 5-FU 敏感，为提高基于 5-FU 的化疗治疗人类癌症的疗效提供了一种潜在策略。
