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A critical role of PI-3K/Akt/JNKs pathway in benzo[a]pyrene diol-epoxide (B[a]PDE)-induced AP-1 transactivation in mouse epidermal Cl41 cells

Oncogene volume 23, pages 3932–3944 (2004)Cite this article

Abstract

Mouse skin tumorigenicity studies indicate that benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) contributes to carcinogenesis as both a tumor initiator and promoter. However, the mechanisms that mediate B[a]PDE tumor promotion effects remain unclear. Our results demonstrated that in mouse epidermal Cl41 cells, B[a]PDE treatment resulted in marked activation of AP-1 and its upstream MAPKs, including ERKs, JNKs and p38K. B[a]PDE exposure also led to activation of phosphotidylinositol 3-kinase (PI-3K), Akt and p70 S6 kinase (p70S6k). B[a]PDE-induced AP-1 transactivation was inhibited by pretreatment of cells with PI-3K inhibitors, wortmannin or Ly294002. In contrast, inhibition of p70S6k with rapamycin did not show any inhibitory effects. An overexpression of dominant-negative mutant of PI-3K, Δp85, impaired B[a]PDE-induced activation of PI-3K, Akt and AP-1 transactivation. Furthermore, an overexpression of dominant-negative Akt mutant, Akt-T308A/S473A, blocked B[a]PDE-induced activation of Akt, AP-1 and JNKs, while it did not affect the activation of p70S6k, ERKs and p38 kinase. These results demonstrated that B[a]PDE was able to induce AP-1 transactivation and this AP-1 induction was specific through PI-3K/Akt/JNKs-dependent and p70S6k-independent pathways. This study also indicated that Akt-T308A/S473A blocks B[a]PDE-induced AP-1 activation specific through impairing JNK pathway. These findings will help us to understand the signal transduction pathways involved in the carcinogenic effects of B[a]PDE.

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Abbreviations

AP-1:

activated protein-1

B[a]P:

benzo[a]pyrene

B[a]PDE:

(±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide

CDE:

chrysene-1,2-diol-3,4-epoxide

5-MCDE:

(±)-anti-5-methylchrysene-1,2-diol-3,4-epoxide

ERKs:

extracellular signal-regulated protein kinases

FBS:

fetal bovine serum

IκBα:

inhibitory subunit kappa-B

IKKβ:

IκB kinase β

JNKs:

c-Jun N-terminal kinases

MAPKs:

mitogen-activated protein kinases

MEM:

Eagle's minimal essential medium

NFκB:

nuclear factor-κB

PKC:

protein kinase C

PAHs:

polycyclic aromatic hydrocarbons

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TPA:

12-O-tetradecanoylphorbol-13-acetate

TNF:

tumor necrosis factor

UV:

ultraviolet

References

  • Albert RE, Miller ML, Cody T, Andringa A, Shukla R and Baxter CS . (1991). Carcinogenesis, 12, 1273–1280.

  • Alessi DR and Downes CP . (1998). Biochim. Biophys. Acta, 1436, 151–164.

  • Aoki M, Schetter C, Himly M, Batista O, Chang HW and Vogt PK . (2000). J. Biol. Chem., 275, 6267–6275.

  • Bernelot-Moens C, Glickman BW and Gordon AJ . (1990). Carcinogenesis, 11, 781–785.

  • Bernstein LR and Colburn N . (1989). Science, 244, 566–569.

  • Bostrom CE, Gerde P, Hanberg A, Jernstrom B, Johansson C, Kyrklund T, Rannug A, Tornqvist M, Victorin K and Westerholm R . (2002). Environ. Health Perspect., 110, 451–488.

  • Bral CM and Ramos KS . (1997). Mol. Pharmacol., 52, 974–982.

  • Bresnick E, McDonald TF, Yagi H, Jerina DM, Levin W, Wood AW and Conney AH . (1977). Cancer Res., 37, 984–990.

  • Buening MK, Wislocki PG, Levin W, Yagi H, Thakker DR, Akagi H, Koreeda M, Jerina DM and Conney AH . (1978). Proc. Natl. Acad. Sci. USA, 75, 5358–5361.

  • Burgering BM and Coffer PJ . (1995). Nature, 376, 599–602.

  • Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R and Soltoff S . (1991). Cell, 64, 281–302.

  • Cantley LC and Neel BG . (1999). Proc. Natl. Acad. Sci. USA, 96, 4240–4245.

  • Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS and Cantley LC . (1990). J. Biol. Chem., 265, 19704–19711.

  • Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM and Vogt PK . (1997). Science, 276, 1848–1850.

  • Conney AH . (1982). Cancer Res., 42, 4875–4917.

  • Conney AH, Chang RL, Jerina DM and Wei SJ . (1994). Drug Metab. Rev., 26, 125–163.

  • Cooper SJ, MacGowan J, Ranger-Moore J, Young MR, Colburn NH and Bowden GT . (2003). Mol. Cancer Res., 1, 848–854.

  • Cosman M, de los Santos C, Fiala R, Hingerty BE, Singh SB, Ibanez V, Margulis LA, Live D, Geacintov NE, Broyde S and Patel DJ . (1992). Proc. Natl. Acad. Sci. USA, 89, 1914–1918.

  • Datta SR, Brunet A and Greenberg ME . (1999). Gen. Dev., 13, 2905–2927.

  • DiGiovanni J . (1992). Pharmacol. Ther., 54, 63–128.

  • Dong Z, Birrer MJ, Watts RG, Matrisian LM and Colburn NH . (1994). Proc. Natl. Acad. Sci. USA, 91, 609–613.

  • Dong Z, Watts RG, Sun Y, Zhan SN and Colburn NH . (1995). Int. J. Oncol., 7, 359–364.

  • Eisenstadt E, Warren AJ, Porter J, Atkins D and Miller JH . (1982). Proc. Natl. Acad. Sci. USA, 79, 1945–1949.

  • Ferrari S, Bannwarth W, Morley SJ, Totty NF and Thomas G . (1992). Proc. Natl. Acad. Sci. USA, 89, 7282–7286.

  • Fukui Y, Saltiel AR and Hanafusa H . (1991). Oncogene, 6, 407–411.

  • Funakoshi-Tago M, Tago K, Sonoda Y, Tominaga S and Kasahara T . (2003). Eur. J. Biochem., 270, 1257–1268.

  • Gonzales M and Bowden GT . (2002). Oncogene, 21, 2721–2728.

  • Hall M, Forrester LM, Parker DK, Grover PL and Wolf CR . (1989). Carcinogenesis, 10, 1815–1821.

  • Han JW, Pearson RB, Dennis PB and Thomas G . (1995). J. Biol. Chem., 270, 21396–21403.

  • Hecht SS, Bondinell WE and Hoffmann D . (1974). J. Natl. Cancer Inst., 53, 1121–1133.

  • Heidelberger C . (1973). Adv. Cancer Res., 18, 317–366.

  • Hoffmann D, Djordjevic MV and Hoffmann I . (1997). Prev. Med., 26, 427–434.

  • Hu Q, Klippel A, Muslin AJ, Fantl WJ and Williams LT . (1995). Science, 268, 100–102.

  • Huang C, Huang Y, Li J, Hu W, Aziz R, Tang MS, Sun N, Cassady J and Stoner GD . (2002). Cancer Res., 62, 6857–6863.

  • Huang C, Li J, Ding M, Leonard SS, Wang L, Castranova V, Vallyathan V and Shi X . (2001). J. Biol. Chem., 276, 40234–40240.

  • Huang C, Li J, Ke Q, Leonard SS, Jiang BH, Zhong XS, Costa M, Castranova V and Shi X . (2002). Cancer Res., 56, 5689–5697.

  • Huang C, Li J, Ma WY and Dong Z . (1999). J. Biol. Chem., 274, 29672–29676.

  • Huang C, Ma WY, Dawson MI, Rincon M, Flavell RA and Dong Z . (1997a). Proc. Natl. Acad. Sci. USA, 94, 5826–5830.

  • Huang C, Ma WY and Dong Z . (1996). Mol. Cell. Biol., 16, 6427–6435.

  • Huang C, Ma WY, Young MR, Colburn N and Dong Z . (1998). Proc. Natl. Acad. Sci. USA, 95, 156–161.

  • Huang C, Schmid PC, Ma WY, Schmid HH and Dong Z . (1997b). J. Biol. Chem., 272, 4187–4194.

  • Jeno P, Ballou LM, Novak-Hofer I and Thomas G . (1988). Proc. Natl. Acad. Sci. USA, 85, 406–410.

  • Jhun BH, Rose DW, Seely BL, Rameh L, Cantley L, Saltiel AR and Olefsky JM . (1994). Mol. Cell. Biol., 14, 7466–7475.

  • Kapeller R and Cantley LC . (1994). BioEssays, 16, 565–576.

  • Karin M, Liu Z and Zandi E . (1997). Curr. Opin. Cell. Biol., 9, 240–246.

  • Kim AH, Yano H, Cho H, Meyer D, Monks B, Margolis B, Birnbaum MJ and Chao MV . (2002). Neuron, 35, 697–709.

  • Kovary K and Bravo R . (1991). Mol. Cell. Biol., 11, 4466–4472.

  • Lee YH, Giraud J, Davis RJ and White MF . (2003). J. Biol. Chem., 278, 2896–2902.

  • Lei W, Yu R, Mandlekar S and Kong AN . (1998). Cancer Res., 58, 2102–2106.

  • Levin W, Wood AW, Wislocki PG, Kapitulnik J, Yagi H, Jerina DM and Conney AH . (1977). Cancer Res., 37, 3356–3361.

  • Li JJ, Westergaard C, Ghosh P and Colburn NH . (1997). Cancer Res., 57, 3569–3576.

  • Merimsky O and Inbar M . (1998). Clin. Dermatol., 16, 585–588.

  • Myers Jr MG and White MF . (1996). Annu. Rev. Pharmacol. Toxicol., 36, 615–658.

  • Nebert DW, Puga A and Vasiliou V . (1993). Ann. NY Acad. Sci., 685, 624–640.

  • Parrish AR, Alejandro NF, Bral CM, Kevin Kerzee J, Bowes RC and Ramos KS . (2002). Biochem. Pharmacol., 64, 31–39.

  • Parrish AR, Fisher R, Bral CM, Burghardt RC, Gandolfi AJ, Brendel K and Ramos KS . (1998). Toxicol. Appl. Pharmacol., 152, 302–308.

  • Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE and Thomas G . (1995). EMBO J., 14, 5279–5287.

  • Phillips DH . (1983). Nature, 303, 468–472.

  • Pitot HC III and Dragan YP . (1996). Casarett and Doull's Toxicology: The Basic Science of Poisons, Klaassen CD (ed) McGraw-Hill, Health Professions Division: New York, pp. 201–267.

    Google Scholar 

  • Proud CG . (1996). Trends Biochem. Sci., 21, 181–185.

  • Reinhard C, Thomas G and Kozma SC . (1992). Proc. Natl. Acad. Sci. USA, 89, 4052–4056.

  • Rodriguez H and Loechler EL . (1993). Carcinogenesis, 14, 373–383.

  • Selkirk JK, Macleod MC, Moore CJ, Mansfield BK, Nikbakht A and Dearstone K . (1982). Mechanisms of Chemical Carcinogenesis, Harris CCA (ed.) Alan R Liss Inc: New York, pp. 331–349.

    Google Scholar 

  • Shepherd PR, Withers DJ and Siddle K . (1998). Biochem. J., 333 (Part 3), 471–490.

  • Shimada T, Gillam EM, Oda Y, Tsumura F, Sutter TR, Guengerich FP and Inoue K . (1999). Chem. Res. Toxicol., 12, 623–629.

  • Sims P and Grover PL . (1974). Adv. Cancer Res., 20, 165–274.

  • Slaga TJ, Bracken WJ, Gleason G, Levin W, Yagi H, Jerina DM and Conney AH . (1979). Cancer Res., 39, 67–71.

  • Smith LE, Denissenko MF, Bennett WP, Li H, Amin S, Tang M and Pfeifer GP . (2000). J. Natl. Cancer Inst., 92, 803–811.

  • Smith MJ and Prochownik EV . (1992). Blood, 79, 2107–2115.

  • Susa M, Olivier AR, Fabbro D and Thomas G . (1989). Cell, 57, 817–824.

  • Tannheimer SL, Ethier SP, Caldwell KK and Burchiel SW . (1998). Carcinogenesis, 19, 1291–1297.

  • Thompson EJ, MacGowan J, Young MR, Colburn N and Bowden GT . (2002). Cancer Res., 62, 3044–3047.

  • Toker A . (2000). Mol. Pharmacol., 57, 652–658.

  • Varticovski L, Daley GQ, Jackson P, Baltimore D and Cantley LC . (1991). Mol. Cell. Biol., 11, 1107–1113.

  • Watts RG, Huang C, Young MR, Li JJ, Dong Z, Pennie WD and Colburn NH . (1998). Oncogene, 17, 3493–3498.

  • Whitman M, Downes CP, Keeler M, Keller T and Cantley L . (1988). Nature, 332, 644–646.

  • Yang JL, Chen RH, Maher VM and McCormick JJ . (1991). Carcinogenesis, 12, 71–75.

  • Yano S, Tokumitsu H and Soderling TR . (1998). Nature, 396, 584–587.

  • Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R and Colburn N . (1999). Proc. Natl. Acad. Sci. USA, 96, 9827–9832.

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Acknowledgements

We thank Jane Galvin for secretarial support. This work was supported in part by grants from National Institutes of Health (NIH)/National Cancer Institute (CA094964, CA103180, and CA112557) and NIH/National Institute of Environmental Health Sciences (ES012451).

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Authors and Affiliations

  1. Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, 10987, NY, USA

    Jingxia Li, Moon-shong Tang & Chuanshu Huang

  2. National Institute of Occupational Health and Poisons Control, Chinese Center for Diseases Control and Prevention, 29 Nan Wei Road, Beijing, 100050, China

    Bingci Liu

  3. Institute for Nutritional Sciences, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai, 200031, China

    Xianglin Shi & Chuanshu Huang

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Li, J., Tang, Ms., Liu, B. et al. A critical role of PI-3K/Akt/JNKs pathway in benzo[a]pyrene diol-epoxide (B[a]PDE)-induced AP-1 transactivation in mouse epidermal Cl41 cells. Oncogene 23, 3932–3944 (2004). https://doi.org/10.1038/sj.onc.1207501

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