Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

Abstract

Colorectal cancer (CRC) is one of the most common and recurrent types of cancer, with high mortality rates. Several clinical trials and meta-analyses have determined that the use of pharmacological inhibitors of cyclooxygenase 2 (COX-2), the enzyme that catalyses the rate-limiting step in the synthesis of prostaglandins (PG) from arachidonic acid, can reduce the incidence of CRC as well as the risk of recurrence of this disease, when used together with commonly used chemotherapeutic agents. These observations suggest that inhibition of COX-2 may be useful in the treatment of CRC, although the current drugs targeting COX-2 are not widely used since they increase the risk of health complications. To overcome this difficulty, a possibility is to identify genes regulated by COX-2 activity that could give an advantage to the cells to form tumors and/or metastasize. The modulation of those genes as effectors of COX-2 may cancel the beneficial effects of COX-2 in tumor transformation and metastasis. A review of the available databases and literature and our own data have identified some interesting molecules induced by prostaglandins or COX-2 that have been also described to play a role in colon cancer, being thus potential pharmacological targets in colon cancer. Among those mPGES-1, DUSP4, and 10, Programmed cell death 4, Trop2, and many from the TGFb and p53 pathways have been identified as genes upregulated in response to COX-2 overexpression or PGs in colon carcinoma lines and overexpressed in colon tumor tissue. Here, we review the available evidence of the potential roles of those molecules in colon cancer in the context of PG/ COX signaling pathways that could be critical mediators of some of the tumor growth and metastasis advantage induced by COX-2. At the end, this may allow defining new therapeutic targets/drugs against CRC that could act specifically against tumor cells and would be effective in the prevention and treatment of CRC, lacking the unwanted side effects of COX-2 pharmacological inhibitors, providing alternative approaches in colon cancer.

Trop2: Jack of All Trades, Master of None

“…Signaling pathways that regulate Trop2 expression includes cyclooxygenase-2 and tumor necrosis factor-α in colon carcinoma cells [ 127 , 128 ], PTEN and lipoxygenase in prostate cells ([ 129 , 130 ], TGF-β in Langerhans cells [ 131 ], and fibroblast growth factor in embryonic lungs [ 132 ]. These pathways are often deregulated during tumorigenesis and may be, therefore, at least partially responsible for modulation of Trop2 expression in malignant cells.…”

Thyroid Tumor: Investigating MicroRNA-21 Gene Suppression in FTC and FTA

“…29 The MMP is a proteolytic enzyme that promote tumor growth and vascularization and are involved in the degradation and remodeling of the extracellular matrix (ECM), in cell migration and metastasis. 30 From the results of the study, metalloproteinase-3 (TIMP3) gene was found to be downregulated in both FTC and FTA. TIMP3 have been previously reported to be downregulated in primary thyrocytes infected with RET/PTC1 retroviral vector 20 and hypermethylated in association with BRAF mutation.…”

“…MiR-21 inhibits metalloproteinases 3 (TIMP3) which suppresses malignancy and inhibits matrix metalloproteinases (MMPs). 29 The MMP is a proteolytic enzyme that promote tumor growth and vascularization and are involved in the degradation and remodeling of the extracellular matrix (ECM), in cell migration and metastasis. 30 From the results of the study, metalloproteinase-3 (TIMP3) gene was found to be downregulated in both FTC and FTA.…”

“…30,32 Two isoforms of COX exist (COX-1 and COX-2), and they play the same cyclooxygenase role but differ in cell inhibition and expression etcetera. 30 COX-2 is upregulated by p53, induced by tumorigenesis, cytokines, and largely undetectable in normal tissues. 30 Elevated MMP expression and COX-2 have been reported in cancerous tissues compared with normal samples, and COX-2 inhibitors have been touted as a strategy for cancer immunotherapy to reduce indoleamine 2,3-dioxygenase 1 (IDO1) overexpression.…”

“…30 COX-2 is upregulated by p53, induced by tumorigenesis, cytokines, and largely undetectable in normal tissues. 30 Elevated MMP expression and COX-2 have been reported in cancerous tissues compared with normal samples, and COX-2 inhibitors have been touted as a strategy for cancer immunotherapy to reduce indoleamine 2,3-dioxygenase 1 (IDO1) overexpression. 30 IDO1 overexpression is a feature of many cancerous conditions and linked to unresponsive immunotherapy due to lack of infiltration of T-cells in the tumor.…”