Abstract
Polycyclic aromatic hydrocarbons are ubiquitous environmental pollutants formed during incomplete combustion of organic material. For example benzo[a]pyrene (B[a]P) is a constituent and contaminant of cigarette smoke, automobile exhaust, industrial waste and even food products. B[a]P is carcinogenic to rodents and humans. B[a]P induces its own metabolism, which generates different metabolites such as the highly reactive electrophilic genotoxin and ultimal carcinogen B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to nucleophilic macromolecules such as proteins and DNA and causes mutations. Multiple defence mechanisms have evolved to protect the cell from DNA damage. Specific signalling pathways operate to detect and repair different kinds of lesions. In case, the damage is poorly removed expansion of damaged cells can be counteracted, e.g., by the inhibition of proliferation or triggering apoptosis. Examples of damage sensors and transducers are stress-activated protein kinases (SAPKs) and the tumour suppressor protein p53. Here, we studied the role of p53 and the pro-apoptotic protein BAX in BPDE-induced cell death by using wild-type- or knock-out-human colon carcinoma cells. As reported previously, we could reconfirm a critical role of p53 in BPDE-induced apoptosis. Furthermore, induced levels of total p53 and its transcriptional target p21 declined at higher BPDE concentrations correlating with reduced rates of apoptosis. Interestingly, increased phosphorylation of p53 at serine 15 remained elevated at higher BPDE concentrations thus disconnecting p53 phosphorylation from downstream apoptosis. Hence, phosphorylation of p53 seems not only to be a more sensitive biomarker of BPDE exposure but might serve other functions unrelated to apoptosis. In addition, we identify BAX as a novel and essential factor to trigger the intrinsic pathway of apoptosis in response to BPDE. Furthermore, BPDE in parallel activates the SAPKs p38 and JNK, which are as well involved in apoptosis. Although several routes of mutual regulation of p53 and SAPK have been described, we present evidence that the SAPK pathway in response to genotoxic stress can unexpectedly operate independently of p53 and controls apoptosis by a novel mechanism possibly downstream of caspases.
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References
Aylon Y, Oren M (2007) Living with p53, dying of p53. Cell 130(4):597–600
Bellamy COC (1997) p53 and apoptosis. Br Med Bull 53(3):522–538
Beneke S, Burkle A (2007) Poly(ADP-ribosyl)ation in mammalian ageing. Nucleic Acids Res 35(22):7456–7465
Brunelle JK, Letai A (2009) Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 122(4):437–441
Chen S, Nguyen N, Tamura K, Karin M, Tukey RH (2003) The role of the Ah receptor and p38 in benzo[a]pyrene-7, 8-dihydrodiol and benzo[a]pyrene-7, 8-dihydrodiol-9, 10-epoxide-induced apoptosis. J Biol Chem 278(21):19526–19533
Chipuk JE, Green DR (2006) Dissecting p53-dependent apoptosis. Cell Death Differ 13(6):994–1002
de Kok T, van Maanen JMS (2000) Evaluation of fecal mutagenicity and colorectal cancer risk. Mutat Res Rev Mutat Res 463(1):53–101
Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27(48):6245–6251
Edwards NT (1983) Polycyclic aromatic hydrocarbons (PAH’s) in the terrestrial environment a review. J Environ Qual 12(4):427–441
Guillen MD, Sopelana P, Partearroyo MA (1997) Food as a source of polycyclic aromatic carcinogens. Rev Environ Health 12(3):133–146
Hattemer-Frey Ha TCC (1992) Benzo-a-pyrene: environmental partitioning and human exposure. Toxicol Ind Health 8(3):213–219
Herrlich P, Karin M, Weiss C (2008) Supreme EnLIGHTenment: damage recognition and signaling in the mammalian UV response. Mol cell 29(3):279–290
Hockley SL, Arlt VM, Jahnke G, Hartwig A, Giddings I, Phillips DH (2008) Identification through microarray gene expression analysis of cellular responses to benzo(a)pyrene and its diol-epoxide that are dependent or independent of p53. Carcinogenesis 29(1):202–210
Junttila MR, Li SP, Westermarck J (2008) Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. Faseb J 22(4):954–965
Lee SK, Kim YS, Song SB, Kim YS (2010) Stabilization and translocation of p53 to mitochondria is linked to Bax translocation to mitochondria in simvastatin-induced apoptosis. Biochem Biophys Res Commun 391(4):1592–1597
Li J, Chen H, Ke Q et al (2004a) Differential effects of polycyclic aromatic hydrocarbons on transactivation of AP-1 and NF-B in mouse epidermal cl41 cells. Mol Carcinog 40(2):104–115
Li J, Tang MS, Liu B, Shi X, Huang C (2004b) A critical role of PI-3 K//Akt//JNKs pathway in benzo[a]pyrene diol-epoxide (B[a]PDE)-induced AP-1 transactivation in mouse epidermal Cl41 cells. Oncogene 23(22):3932–3944
Lorenzo HK, Susin SA (2004) Mitochondrial effectors in caspase-independent cell death. FEBS Lett 557(1–3):14–20
Mathiasen IS, Jäättelä M (2002) Triggering caspase-independent cell death to combat cancer. Trends Mol Med 8(5):212–220
Menendez D, Inga A, Resnick MA (2009) The expanding universe of p53 targets. Nat Rev Cancer 9(10):724–737
Page TJ, O’Brien S, Jefcoate CR, Czuprynski CJ (2002) 7, 12-Dimethylbenz[a]anthracene induces apoptosis in murine pre-B cells through a caspase-8 dependent pathway. Mol Pharmacol 62(2):313–319
Phillips DH (1999) Polycyclic aromatic hydrocarbons in the diet. Mutat Res Genet Toxicol Environ Mutagen 443(1–2):139–147
Pietsch EC, Sykes SM, McMahon SB, Murphy ME (2008) The p53 family and programmed cell death. Oncogene 27(50):6507–6521
Pop C, Salvesen GS (2009) Human caspases: activation, specificity, and regulation. J Biol Chem 284(33):21777–21781
Ramesh A, Walker SAS, Hood DB, Guillen MD, Schneider K, Weyand EH (2004) Bioavailability and risk assessment of orally ingested polycyclic aromatic hydrocarbons. Int J Toxicol 23(5):301–333
Rubin H (2001) Synergistic mechanisms in carcinogenesis by polycyclic aromatic hydrocarbons and by tobacco smoke: a bio-historical perspective with updates. Carcinogenesis 22(12):1903–1930
Ryu HY, Emberley JK, Schlezinger JJ, Allan LL, Na S, Sherr DH (2005) Environmental chemical-induced bone marrow B cell apoptosis: death receptor-independent activation of a caspase-3 to caspase-8 pathway. Mol Pharmacol 68(4):1087–1096
Schreck I, Chudziak D, Schneider S et al (2009) Influence of aryl hydrocarbon- (Ah) receptor and genotoxins on DNA repair gene expression and cell survival of mouse hepatoma cells. Toxicology 259(3):91–96
Schreck I, Al-Rawi M, Mingot JM et al (2011) c-Jun localizes to the nucleus independent of its phosphorylation by and interaction with JNK and vice versa promotes nuclear accumulation of JNK. Biochem Biophys Res Commun 407(4):735–740
Solhaug A, Refsnes M, Holme JA (2004a) Role of cell signalling involved in induction of apoptosis by benzo[a]pyrene and cyclopenta[c, d]pyrene in Hepa1c1c7 cells. J Cell Biochem 93(6):1143–1154
Solhaug A, Refsnes M, Lag M, Schwarze PE, Husoy T, Holme JA (2004b) Polycyclic aromatic hydrocarbons induce both apoptotic and anti-apoptotic signals in Hepa1c1c7 cells. Carcinogenesis 25(5):809–819
Solhaug A, Ovrebo S, Mollerup S et al (2005) Role of cell signaling in B[a]P-induced apoptosis: characterization of unspecific effects of cell signaling inhibitors and apoptotic effects of B[a]P metabolites. Chem Biol Interact 151(2):101–119
Toledo F, Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6(12):909–923
Ura S, Nishina H, Gotoh Y, Katada T (2007) Activation of the c-Jun N-terminal kinase pathway by MST1 is essential and sufficient for the induction of chromatin condensation during apoptosis. Mol Cell Biol 27(15):5514–5522
Vaseva AV, Moll UM (2009) The mitochondrial p53 pathway. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1787(5):414–420
Weiss C, Bohmann D (2004) Deregulated repression of c-Jun provides a potential link to its role in tumorigenesis. Cell Cycle 3(2):111–113
Weiss C, Schneider S, Wagner EF, Zhang X, Seto E, Bohmann D (2003) JNK phosphorylation relieves HDAC3-dependent suppression of the transcriptional activity of c-Jun. EMBO J 22(14):3686–3695
Xiao H, Singh SV (2007) p53 Regulates cellular responses to environmental carcinogen benzo[a]pyrene-7, 8-diol-9, 10-epoxide in human lung cancer cells. Cell Cycle 6(14):1753–1761
Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B (2000) Role of BAX in the apoptotic response to anticancer agents. Science 290(5493):989–992
Zhang Y, Tao S, Shen H, Ma J (2009) Inhalation exposure to ambient polycyclic aromatic hydrocarbons and lung cancer risk of Chinese population. Proc Natl Acad Sci 106(50):21063–21067
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We thank Dorit Mattern for technical assistance.
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Donauer, J., Schreck, I., Liebel, U. et al. Role and interaction of p53, BAX and the stress-activated protein kinases p38 and JNK in benzo(a)pyrene-diolepoxide induced apoptosis in human colon carcinoma cells. Arch Toxicol 86, 329–337 (2012). https://doi.org/10.1007/s00204-011-0757-3
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DOI: https://doi.org/10.1007/s00204-011-0757-3