Diosgenin exerts anti-tumor effects through inactivation of cAMP/PKA/ CREB signaling pathway in colorectal cancer
Diosgenin exerts anti-tumor effects through inactivation of cAMP/PKA/ CREB signaling pathway in colorectal cancer
复制标题
薯蓣皂苷元通过失活结直肠癌中的 cAMP/PKA/CREB 信号通路发挥抗肿瘤作用
DOI：
10.1016/j.ejphar.2021.174370
复制
发表时间：
2021-07-30
影响因子：
5
通讯作者：
Shen, Dong-Yan
中科院分区：
文献类型：
--
作者：
Li, Si-Yang;Shang, Jin;Shen, Dong-Yan
结直肠癌（Colorectal cancer， CRC）是最致命的胃肠道肿瘤，迫切需要探索有效的治疗药物。薯蓣皂苷元（Diosgenin， DSG）作为一种新的甾体药物，在包括结直肠癌在内的多种肿瘤中具有抗肿瘤活性。然而，DSG抑制CRC的潜在机制仍有待进一步揭示。本研究中，我们报道了DSG以剂量和时间依赖的方式抑制CRC细胞增殖，通过调节p53和Bcl-2家族蛋白表达介导线粒体凋亡途径诱导凋亡，通过降低基质金属蛋白酶MMP-9 (matrix metalloproteinase, MMP-9)，通过介导GLUT3和GLUT4等葡萄糖转运体（GLUT），以及丙酮酸羧化酶PC下调来抑制迁移和侵袭，从而抑制好氧糖酵解。有趣的是，机制研究表明，涉及DSG的表型在CRC细胞中抑制cAMP/PKA/ CREB通路，从而抑制CREB的磷酸化，从而调节上述基因的转录。最后，裸鼠异种移植肿瘤模型进一步表明，DSG在体内可以很好地抑制CRC细胞的生长，且无明显的副作用。综上所述，我们揭示了DSG通过cAMP/PKA/CREB途径抑制CRC细胞的独特机制，DSG是一种很有前景的CRC治疗候选药物。
Colorectal cancer (CRC) is the most fatal gastrointestinal tumor and it is urge to explore powerful drugs for the treatment. Diosgenin (DSG) as a new steroidal had been reported exerts anti-tumor activity in multiple cancers, including CRC. However, the potential mechanism of DSG suppresses CRC remains further to be revealed. Here, we reported that DSG inhibited proliferation of CRC cells in dose- and time-dependent manner, induced apoptosis by modulating p53 and Bcl-2 family proteins expression to mediate mitochondrial apoptosis pathway, suppressed migration and invasion by reducing MMP-9 (matrix metalloproteinase) and decreased aerobic glycolysis by mediating glucose transporter (GLUT) like GLUT3 and GLUT4, and pyruvate carboxylase PC downregulation. Intriguingly, mechanistic study suggests those phenotypes involved DSG inhibited cAMP/PKA/ CREB pathway in CRC cells, and result to inhibit the phosphorylation of CREB to regulate the transcription of genes above-mentioned. Finally, nude mice xenograft tumor model further indicated that DSG could be a great agent to suppress the growth of CRC cells in vivo and have no obvious side effects. Taken together, we revealed a unique mechanism that DSG suppresses CRC cells through cAMP/PKA/CREB pathway and DSG is a promising candidate drug for CRC treatment.