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(min/+) 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. (C) 2019 Published by Elsevier Inc.