ABSTRACT
Title
Microsomal Prostaglandin E synthase-1 modulates the EGFR-mediated tumor growth
Authors
F. Finetti1, E. Terzuoli1, A. Giachetti1 M. Ziche1 and S. Donnini1
1Dept of Biotechnology. Section of Pharmacology Toxicology and Chemotherapy. University of Siena
1Dept of Biotechnology. Section of Pharmacology Toxicology and Chemotherapy. University of Siena
Abstract
Prostaglandin E2 (PGE-2) play a key role in cancer biology. Cyclooxygense-2 over-expression (COX-2), and high levels of PGE-2 are often associated with the growth and aggressiveness of several human cancers. Regarding PGE-2 production, recent investigations have focused on PGE-2 synthases (mPGES-1, mPGES-2 and cPGES), and specifically on mPGES-1, the only inducible enzyme among those so far identified in cells. Whereas cPGEs and mPGEs-2 areconstitutively expressed at relatively low levels, mPGES-1 is highlyinducible by pro-inflammatory stimuli and it is over-expressed in tumor specimens. Here, we investigated mPGES-1 regulation in cultured epithelial tumor cells exposed to epidermal growth factor (EGF), an oncogene product responsible for tumorigenesis in a wide array of solid tumors.
In particular, we investigated the mechanism controlling the mPGES-1 expression in HT-29 (colorectal cancer cells), A431 (epidermoid cancer cells) and A549 (lung cancer cells) tumor cells following EGFR stimulation, focusing on the activity of early growth response protein-1 (Egr-1), a transcription factor readily up-regulated by EGF. The Egr-1 rise provoked the over-expression of mPGES-1 messenger and protein, and enhanced PGE-2 formation. These changes were suppressed either by silencing Egr-1, or by up-stream blockade of EGFR or ERK1/2 signals. Further, in a clonogenic assay on tumor cells, EGF induced a florid tumorigenic phenotype, which regressed when mPGES-1 was knocked down. In conclusion, these findings provide evidence that a tight cooperation between the EGF/EGFR and mPGES-1 leads to a significant tumorigenic gain in epithelial cells, and provide clues for combinatorial therapy in cancer treatment.
In particular, we investigated the mechanism controlling the mPGES-1 expression in HT-29 (colorectal cancer cells), A431 (epidermoid cancer cells) and A549 (lung cancer cells) tumor cells following EGFR stimulation, focusing on the activity of early growth response protein-1 (Egr-1), a transcription factor readily up-regulated by EGF. The Egr-1 rise provoked the over-expression of mPGES-1 messenger and protein, and enhanced PGE-2 formation. These changes were suppressed either by silencing Egr-1, or by up-stream blockade of EGFR or ERK1/2 signals. Further, in a clonogenic assay on tumor cells, EGF induced a florid tumorigenic phenotype, which regressed when mPGES-1 was knocked down. In conclusion, these findings provide evidence that a tight cooperation between the EGF/EGFR and mPGES-1 leads to a significant tumorigenic gain in epithelial cells, and provide clues for combinatorial therapy in cancer treatment.