Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, China; Department of Hepatobiliary Surgery, Wuhan First Hospital, China.
Department of Neurosurgery, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, China.
Biochem Biophys Res Commun. 2019 Sep 10;517(1):1-7. doi: 10.1016/j.bbrc.2018.01.061. Epub 2018 Jan 13.
For colorectal cancer (CRC) patients, local and systemic inflammatory responses have been extensively reported to closely associate with patient survival. However, the specific signaling pathways responsible for carcinogenic responses are unclear. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of PI3K/AKT pathway that is gradually inactivated in cancers through mutation, loss of heterozygosity and others epigenetic mechanisms. In addition, COX and LOX metabolic pathways of arachidonic acid (AA) play a crucial role in promoting adenoma development. The aim of this study is to clarify the relationship of COX, LOX and PTEN/PI3K/AKT pathway. Results showed that the over-expressed COX and LOX in cancer cells can be targeted to decrease the expression of PTEN. After using corresponding inhibitors, this condition was significantly improved and promoted apoptosis, inhibited invasion, proliferation and the production of reactive oxygen species. And for COX-2-/- or 5-LOX-/- Apc mice, the PI3K/AKT pathway was further inhibited via promoting PTEN. Furthermore, weakened oxidative stress, inhibited adenoma growth, and improved survival rate. All findings indicated that PTEN was indirectly targeted by these enzyme inhibitors and acted as the potential therapeutic target for colorectal cancer therapy. In short, COX-2 or 5-LOX deletion and its inhibitors enhanced activity of PTEN and suppressed cell and adenoma progression through PI3K/AKT pathway in colorectal cancer.
对于结直肠癌（CRC）患者，局部和全身炎症反应与患者的生存密切相关，这已经得到了广泛的报道。然而，导致致癌反应的确切信号通路尚不清楚。磷酸酶和张力蛋白同源物缺失的染色体 10（PTEN）是 PI3K/AKT 通路的负调节剂，它通过突变、杂合性丢失和其他表观遗传机制逐渐在癌症中失活。此外，花生四烯酸（AA）的 COX 和 LOX 代谢途径在促进腺瘤发展中起着至关重要的作用。本研究旨在阐明 COX、LOX 和 PTEN/PI3K/AKT 通路之间的关系。结果表明，癌细胞中过表达的 COX 和 LOX 可以被靶向以降低 PTEN 的表达。使用相应的抑制剂后，这种情况得到了明显改善，促进了细胞凋亡，抑制了侵袭、增殖和活性氧的产生。对于 COX-2-/-或 5-LOX-/-Apc 小鼠，PI3K/AKT 通路通过促进 PTEN 进一步受到抑制。此外，减弱氧化应激、抑制腺瘤生长并提高生存率。所有发现表明，这些酶抑制剂间接靶向 PTEN，并作为结直肠癌治疗的潜在治疗靶点。简而言之，COX-2 或 5-LOX 缺失及其抑制剂通过 PI3K/AKT 通路增强了 PTEN 的活性，并抑制了结直肠癌细胞和腺瘤的进展。
