Zhao Pan, Shen Yao, Li Mengyang, Dan Hanjun, Zhao Zhiming, Zhang Jian
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China.
The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
Front Pharmacol. 2022 May 27;13:793499. doi: 10.3389/fphar.2022.793499. eCollection 2022.
The potential role of tadalafil, a PDE5 inhibitor, in anticancer activity and prolonged survival has been proposed. However, the systematic effects of tadalafil in colorectal cancer were not fully understood. In this study, we assessed the anti-tumor activity of tadalafil in human colorectal cancer cells. A systematic perspective of the tadalafil-induced anti-tumor mechanism was provided by the integration of transcriptomics and metabolomics. We found that differentially expressed genes (DEGs) were mainly involved in microRNAs in cancer, purine metabolism, glycosphingolipid biosynthesis, arginine biosynthesis, and amino acid metabolism. Amino acid metabolism, especially alanine, aspartate, and glutamate metabolism was the most of the differentially accumulated metabolites (DAMs) through the analysis of metabolomics. The conjoint analysis of DEGs and DAMs presented that they were also mainly involved in alanine, aspartate, and glutamate metabolism. Amino acid metabolism-related genes, , were significantly decreased after tadalafil treatment. In particular, the disturbance of alanine, aspartate, and glutamate metabolism may be the explanation for the major mechanism resulting from tadalafil anti-tumor activity.
已有人提出磷酸二酯酶5（PDE5）抑制剂他达拉非在抗癌活性和延长生存期方面的潜在作用。然而，他达拉非在结直肠癌中的系统性作用尚未完全明确。在本研究中，我们评估了他达拉非对人结肠癌细胞的抗肿瘤活性。通过整合转录组学和代谢组学，提供了他达拉非诱导的抗肿瘤机制的系统性观点。我们发现，差异表达基因（DEG）主要涉及癌症中的微小RNA、嘌呤代谢、糖鞘脂生物合成、精氨酸生物合成和氨基酸代谢。通过代谢组学分析，氨基酸代谢，尤其是丙氨酸、天冬氨酸和谷氨酸代谢是差异积累代谢物（DAM）中占比最大的。DEG和DAM的联合分析表明，它们也主要涉及丙氨酸、天冬氨酸和谷氨酸代谢。他达拉非治疗后，与氨基酸代谢相关的基因显著减少。特别是，丙氨酸、天冬氨酸和谷氨酸代谢的紊乱可能是他达拉非抗肿瘤活性产生主要机制的解释。
