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PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the family of programmed cell death-inducing cytokines. Apo2L/TRAIL induces apoptosis in a wide variety of tumor cells. Tumor cells that are resistant to Apo2L/TRAIL-induced apoptosis can be sensitized by chemotherapeutic drugs and other agents via an unknown mechanism. Here we report that PG490 (triptolide), a diterpene triepoxide extracted from the Chinese herb Tripterygium wilfordii and used in traditional Chinese medicine, sensitizes lung cancer but not normal human bronchial epithelial cells to Apo2L/TRAIL-induced apoptosis. Sensitization was accompanied by caspase-3 and caspase-8 activation, whereas no cleavage of caspase-9 was observed. Determination of cell surface receptors by flow cytometry demonstrated no difference in Apo2L/TRAIL-R1 and -R2 expression, the two receptors with functional death domains, between resistant and sensitized cells. In cells treated with the combination of Apo2L/TRAIL and PG490, we observed activation of ERK2, a member of the mitogen-activated protein kinase family. Furthermore, sensitization could be blocked by the ERK inhibitor U0126 but not the p38 inhibitor SB203580, suggesting that activation of ERK2 is required for this effect. In addition, sensitization of lung cancer cells was also seen in ex vivo culture of lung cancer tissue from four patients who underwent surgery. Immunohistochemical staining showed a clear reduction in proliferation cell nuclear antigen (PCNA) in tissue treated with Apo2L/TRAIL and PG490. In conclusion, apoptosis induced by the combination of Apo2L/TRAIL and PG490 warrants further evaluation as a potential new strategy for the treatment of lung cancer.

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References

  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z and Schwall RH . (1999). J. Clin. Invest, 104, 155–162.

  • Chang L and Karin M . (2001). Nature, 410, 37–40.

    Article  CAS  Google Scholar 

  • Chang WT, Kang JJ, Lee KY, Wei K, Anderson E, Gotmare S, Ross JA and Rosen GD . (2001). J. Biol. Chem., 276, 2221–2227.

  • Cottom J, Salvador LM, Maizels ET, Reierstad S, Park Y, Carr DW, Davare MA, Hell JW, Palmer SS, Dent P, Kawakatsu H, Ogata M and Hunzicker-Dunn M . (2003). J. Biol. Chem., 278, 7167–7179.

  • English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S and Cobb MH . (1999). Exp. Cell Res., 253, 255–270.

  • Evdokiou A, Bouralexis S, Atkins GJ, Chai F, Hay S, Clayer M and Findlay DM . (2002). Int. J. Cancer, 99, 491–504.

    Article  CAS  Google Scholar 

  • Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG and Kao PN . (2000). Am. J. Respir. Crit. Care Med., 162, 2252–2258.

  • Frese S, Brunner T, Gugger M, Uduehi A and Schmid RA . (2002). J. Thorac. Cardiovasc. Surg., 123, 168–174.

  • Gliniak B and Le T . (1999). Cancer Res., 59, 6153–6158.

  • Greenlee RT, Hill-Harmon MB, Murray T and Thun M . (2001). CA Cancer J. Clin., 51, 15–36.

  • Griffith TS, Fialkov JM, Scott DL, Azuhata T, Williams RD, Wall NR, Altieri DC and Sandler AD . (2002). Cancer Res., 62, 3093–3099.

  • Griffith TS and Lynch DH . (1998). Curr. Opin. Immunol., 10, 559–563.

  • Huynh PN, Hikim AP, Wang C, Stefonovic K, Lue YH, Leung A, Atienza V, Baravarian S, Reutrakul V and Swerdloff RS . (2000). J. Androl., 21, 689–699.

  • Ishiwata N, Jinn Y, Tsukada Y, Inase N, Ichioka M and Yoshizawa Y . (2000). Anticancer Res., 20, 1445–1450.

  • Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR and Strom SC . (2000). Nat. Med., 6, 564–567.

  • Kim Y, Suh N, Sporn M and Reed JC . (2002). J. Biol. Chem., 277, 22320–22329.

    Article  CAS  Google Scholar 

  • Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ and Ashkenazi A . (2000). Immunity, 12, 611–620.

    Article  CAS  Google Scholar 

  • Krajewska M, Wang HG, Krajewski S, Zapata JM, Shabaik A, Gascoyne R and Reed JC . (1997). Cancer Res., 57, 1605–1613.

  • Lee KY, Chang W, Qiu D, Kao PN and Rosen GD . (1999). J. Biol. Chem., 274, 13451–13455.

    Article  CAS  Google Scholar 

  • Lee KY, Park JS, Jee YK and Rosen GD . (2002a). Exp. Mol. Med., 34, 462–468.

  • Lee MW, Park SC, Yang YG, Yim SO, Chae HS, Bach JH, Lee HJ, Kim KY, Lee WB and Kim SS . (2002b). FEBS Lett., 512, 313–318.

  • Lee YJ, Lee KH, Kim HR, Jessup JM, Seol DW, Kim TH, Billiar TR and Song YK . (2001). Oncogene, 20, 1476–1485.

    Article  CAS  Google Scholar 

  • Leverkus M, Neumann M, Mengling T, Rauch CT, Brocker EB, Krammer PH and Walczak H . (2000). Cancer Res., 60, 553–559.

  • MacKeigan JP, Collins TS and Ting JP . (2000). J. Biol. Chem., 275, 38953–38956.

    Article  CAS  Google Scholar 

  • McCullagh P and Nelder JA . (1989). Monographs on Statistics and Applied Probability, Chapman and Hall, 2nd edition, London.

    Google Scholar 

  • Nam SY, Amoscato AA and Lee YJ . (2002). Oncogene, 21, 337–346.

    Article  CAS  Google Scholar 

  • Nesterov A, Ivashchenko Y and Kraft AS . (2002). Oncogene, 21, 1135–1140.

    Article  CAS  Google Scholar 

  • Rohn TA, Wagenknecht B, Roth W, Naumann U, Gulbins E, Krammer PH, Walczak H and Weller M . (2001). Oncogene, 20, 4128–4137.

    Article  Google Scholar 

  • Scaffidi C, Schmitz I, Krammer PH and Peter ME . (1999). J. Biol. Chem., 274, 1541–1548.

    Article  CAS  Google Scholar 

  • Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, Krammer PH and Walczak H . (2000). Immunity, 12, 599–609.

    Article  CAS  Google Scholar 

  • Stadheim TA, Xiao H and Eastman A . (2001). Cancer Res., 61, 1533–1540.

  • Tran SE, Holmstrom TH, Ahonen M, Kahari VM and Eriksson JE . (2001). J. Biol. Chem., 276, 16484–16490.

    Article  CAS  Google Scholar 

  • Walczak H and Krammer PH . (2000). Exp. Cell Res., 256, 58–66.

  • Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999). Nat. Med., 5, 157–163.

  • Wang X, Martindale JL and Holbrook NJ . (2000). J. Biol. Chem., 275, 39435–39443.

    Article  CAS  Google Scholar 

  • Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C and Smith CA . et al. (1995). Immunity, 3, 673–682.

    Article  CAS  Google Scholar 

  • Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME . (1995). Science, 270, 1326–1331.

    Article  CAS  Google Scholar 

  • Xiang H, Fox JA, Totpal K, Aikawa M, Dupree K, Sinicropi D, Lowe J and Escandon E . (2002). Oncogene, 21, 3611–3619.

    Article  CAS  Google Scholar 

  • Yang Y, Liu Z, Tolosa E, Yang J and Li L . (1998). Immunopharmacology, 40, 139–149.

    Article  CAS  Google Scholar 

  • Zhang XD, Franco A, Myers K, Gray C, Nguyen T and Hersey P . (1999). Cancer Res., 59, 2747–2753.

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Acknowledgements

We thank Dr Matthias Gugger, Institute of Pathology, Berne, for the assessment of normal and cancer lung tissue, Jacob Zbären, Department of Clinical Research, Berne, for exceptional technical assistance in immunohistochemistry, and Dr Andreas Marti, Novartis Basel, for discussions and support in caspase-3 activity test. We are grateful to Professor Peter Krammer, German Cancer Research Center, Heidelberg, for providing the caspase-8 antibody. This work was supported by Grants from the Bernese Cancer League (BKL 61), Novartis Foundation (00B33), and the National Cancer Institute (CA 69381).

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Correspondence to Steffen Frese.

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Frese, S., Pirnia, F., Miescher, D. et al. PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2. Oncogene 22, 5427–5435 (2003). https://doi.org/10.1038/sj.onc.1206842

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