Cyclin D1 Induction by Benzo[a]pyrene-7,8-diol-9,10-epoxide via the Phosphatidylinositol 3-Kinase/Akt/MAPK- and p70s6k-dependent Pathway Promotes Cell Transformation and Tumorigenesis

Jin Ding,Beifang Ning,Wenfeng Gong,Wen Wen,Kun Wu,Junqing Liang,Guoping He,Shanna Huang,Wen Sun,Tao Han,Lei Huang,Guangwen Cao,Mengchao Wu,Weifen Xie,Hongyang Wang

doi:10.1074/jbc.m109.046417

Jin Ding, Beifang Ning + Show 13 more

Open Access

https://doi.org/10.1074/jbc.m109.046417

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Abstract

Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), the major metabolite of B[a]P, has been well recognized as one ubiquitous carcinogen, but the molecular mechanism involved in its carcinogenic effect remains obscure. In the present study, we found that bronchial epithelial cells (Beas-2B) and hepatocytes treated with B[a]PDE presented a significant increase of cyclin D1 expression. Moreover, Akt, p70(s6k), and MAPKs including JNK, Erks, and p38 were notably activated in B[a]PDE-treated Beas-2B cells, whereas NF-kappaB, NFAT, and Egr-1 were not. Our results demonstrated that JNK and Erks were required in B[a]PDE-induced cyclin D1 expression because the inhibition of JNK or Erks by a selective chemical inhibitor or dominant negative mutant robustly impaired the cyclin D1 induction by B[a]PDE. Furthermore, we found that overexpression of the dominant negative mutant of p85 (regulatory subunit of phosphatidylinositol 3-kinase) or Akt dramatically suppressed B[a]PDE-induced JNK and Erk activation as well as cyclin D1 expression, suggesting that cyclin D1 induction by B[a]PDE is via the phosphatidylinositol 3-kinase/Akt/MAPK-dependent pathway. In addition, we clarified that p70(s6k) is also involved in B[a]PDE-induced cyclin D1 expression because rampamycin pretreatment dramatically reduced cyclin D1 induction by B[a]PDE. More importantly, we demonstrated that up-regulated cyclin D1 by B[a]PDE plays a critical role in oncogenic transformation and tumorigenesis of Beas-2B cells. These results not only broaden our knowledge of the molecular mechanism of B[a]PDE carcinogenicity but also lead to the further study of chemoprevention of B[a]PDE-associated human cancers.

Highlights

Fossil fuels [1, 2]
Considering liver is the primary target organ for ingested B[a]P, we examined the cyclin D1 expression in hepatocytes exposed to B[a]PDE, and the results verified that B[a]PDE was able to up-regulate cyclin D1 expression in L02 hepatocytes (Fig. 1, E–G)
We found that phosphorylation of Akt, p70s6k, and MAPKs (Fig. 2, A–C) were significant enhanced in Beas-2B cells upon B[a]PDE exposure, whereas no obvious activation of Egr-1, NF-␬B, or NFAT was observed (Fig. 2, D–F)

Summary

Introduction

Fossil fuels [1, 2]. Benzo[a]pyrene (B[a]P),3 as the first identified carcinogenic component of polycyclic aromatic hydrocarbons, is the most extensively studied carcinogen in cigarette smoke and has been regarded as a critical mediator of lung cancer for a long time [3, 4]. These data demonstrated that Akt, p70s6k, and MAPKs might be implicated in B[a]PDE-induced cyclin D1 expression. JNK and Erks Are Required in B[a]PDE-induced Cyclin D1 Expression, but p38 Is Not—It has been well demonstrated that MAPK family, consisting of JNK, Erks, and p38, modulates the activation of signaling cascades by phosphorylating various transcription factors, which in turn regulate the target gene expression [25, 26].

Results

Conclusion