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First published on November 17, 2006; DOI: 10.1124/mol.106.032078

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Received for publication October 24, 2006.
Revised November 16, 2006.
Accepted for publication November 17, 2006.

Benzo[a]pyrene-7,8-dihydrodiol promotes checkpoint activation and G2/M arrest in human bronchoalveolar carcinoma H358 cells

M. Cecilia Caino 1, Jose Luis Oliva 1, Hao Jiang 1, Trevor M. Penning 1, Marcelo G. Kazanietz 1*

1 University of Pennsylvania School of Medicine

* Address correspondence to: E-mail: marcelo{at}spirit.gcrc.upenn.edu

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are potent carcinogens that require metabolic activation inside cells. The proximate carcinogens PAH-diols can be converted to o-quinones by aldo-keto reductases (AKRs) or to diol-epoxides by cytochrome P450 (CYP) enzymes. We assessed the effect of BP-7,8-dihydrodiol (BPD) on proliferation in p53-null bronchoalveolar carcinoma H358 cells. BPD treatment led to a significant inhibition of proliferation and arrest in G2/M in H358 cells. The relative contribution of the AKR and CYP pathways to cell cycle arrest was assessed. Overexpression of AKR1A1 did not affect cell proliferation or cell cycle progression, and BP-7,8-dione (BPQ) did not cause any noticeable effect on cell growth, suggesting that AKR1A1 metabolic products were not involved in the anti-proliferative effect of BPD. On the other hand, blockade of CYP induction or inhibition of CYP activity greatly impaired the effect of BPD. Moreover, CYP induction by TCDD significantly enhanced the anti-proliferative effect of BPD. Mechanistic studies revealed that BPD caused a DNA damage response, Chk1 activation, and accumulation of phospho-Cdc2 (Y15) in H358 cells, effects that were impaired by an ATM/ATR inhibitor. Similar results were observed in human bronchoepithelial BEAS-2B cells, arguing for analogous mechanisms in tumorigenic and immortalized non-tumorigenic cells lacking functional p53. Our data suggest that a p53-independent pathway operates in lung epithelial cells in response to BPD that involves CYPs induction and subsequent activation of the ATR/ATM/Chk1 damage checkpoint pathway and cell cycle arrest in G2/M.


Key words: Cytochrome P450, DNA damage and repair, Reactive intermediates, Mechanisms of cell killing/apoptosis


This article has been cited by other articles:


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S. K. Srivastava, P. Bansal, T. Oguri, J. S. Lazo, and S. V. Singh
Cell Division Cycle 25B Phosphatase Is Essential for Benzo(a)Pyrene-7,8-Diol-9,10-Epoxide Induced Neoplastic Transformation
Cancer Res., October 1, 2007; 67(19): 9150 - 9157.
[Abstract] [Full Text] [PDF]


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