Faculty Collaboration Database

Differential requirement of signal pathways for benzo[a]pyrene (B[a]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells. Carcinogenesis 2005 Jun;26(6):1035-43

Date

02/19/2005

Pubmed ID

15718251

DOI

10.1093/carcin/bgi052

Scopus ID

2-s2.0-22344453630 (requires institutional sign-in at Scopus site)   28 Citations

Abstract

Overexpression of inducible nitric oxide synthase (iNOS) has been reported in several human cancers, including esophageal squamous cell carcinoma (SCC). Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon carcinogen found in tobacco smoke and in the environment, induces cancer in multiple organ sites in animals and may be a causative agent for certain human cancers, such as esophageal cancer. In the present study, the effects of B[a]P on the induction of iNOS and the signaling pathways that lead to the induction were investigated in cultured rat esophageal epithelial (RE-149) cells. Treatment of RE-149 cells with B[a]P led to a marked increase in the expression of iNOS. The induction of iNOS by B[a]P was found to occur through an extracellular signal-regulated protein kinases (ERKs)-dependent pathway, since inhibition of ERKs by either pretreatment of RE-149 cells with PD98059, an inhibitor of ERKs upstream kinase MEK1/2, or overexpression of DN-ERK2, blocked the induction of iNOS by B[a]P. Furthermore, impairing nuclear factor-kappaB (NFkappaB) activation by either NEMO-BDBP, an NFkappaB specific inhibitor, or overexpression of DN-IkappaBalpha or IKK-KM markedly inhibited the expression of B[a]P-induced iNOS, suggesting that the NFkappaB pathway is also required for the induction of iNOS by B[a]P. In addition, treatment of RE-149 cells with either SB202190, a p38 kinase inhibitor, or c-JunN-terminal kinase inhibitor II, resulted in an increased induction of iNOS. Pretreatment of RE-149 cells with wortmannin, a PI-3K inhibitor, or with rapamycin, an mTOR/p70S6K pathway inhibitor, had no effect on the expression of iNOS. These results suggest that B[a]P initiates the signaling pathways leading to the induction of iNOS in cultured rat esophageal epithelial cells. In view of the potential role of iNOS in the development of esophageal SCC in humans, we speculate that the induction of iNOS by B[a]P may be one mechanism by which B[a]P could produce carcinogenic effects in the human esophagus.

Author List

Chen J, Yan Y, Li J, Ma Q, Stoner GD, Ye J, Huang C

MESH terms used to index this publication - Major topics in bold

Animals
Benzo(a)pyrene
Carcinogens
Cell Line
Dose-Response Relationship, Drug
Enzyme Induction
Epithelial Cells
Esophagus
Mitogen-Activated Protein Kinases
NF-kappa B
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Phosphatidylinositol 3-Kinases
Protein Kinases
Rats
Ribosomal Protein S6 Kinases, 70-kDa
Signal Transduction
TOR Serine-Threonine Kinases
Time Factors