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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
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.
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.
Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ and Ashkenazi A . (2000). Immunity, 12, 611–620.
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.
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.
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.
McCullagh P and Nelder JA . (1989). Monographs on Statistics and Applied Probability, Chapman and Hall, 2nd edition, London.
Nam SY, Amoscato AA and Lee YJ . (2002). Oncogene, 21, 337–346.
Nesterov A, Ivashchenko Y and Kraft AS . (2002). Oncogene, 21, 1135–1140.
Rohn TA, Wagenknecht B, Roth W, Naumann U, Gulbins E, Krammer PH, Walczak H and Weller M . (2001). Oncogene, 20, 4128–4137.
Scaffidi C, Schmitz I, Krammer PH and Peter ME . (1999). J. Biol. Chem., 274, 1541–1548.
Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, Krammer PH and Walczak H . (2000). Immunity, 12, 599–609.
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.
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.
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.
Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME . (1995). Science, 270, 1326–1331.
Xiang H, Fox JA, Totpal K, Aikawa M, Dupree K, Sinicropi D, Lowe J and Escandon E . (2002). Oncogene, 21, 3611–3619.
Yang Y, Liu Z, Tolosa E, Yang J and Li L . (1998). Immunopharmacology, 40, 139–149.
Zhang XD, Franco A, Myers K, Gray C, Nguyen T and Hersey P . (1999). Cancer Res., 59, 2747–2753.
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).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206842
Keywords
This article is cited by
-
Pulmonary delivery of triptolide-loaded liposomes decorated with anti-carbonic anhydrase IX antibody for lung cancer therapy
Scientific Reports (2017)
-
Ethanolic extract of Descurainia sophia seeds sensitizes A549 human lung cancer cells to TRAIL cytotoxicity by upregulating death receptors
BMC Complementary and Alternative Medicine (2016)
-
Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-XL/p53-mediated amplification mechanisms
Cell Death & Disease (2014)
-
Selective tumor cell killing by triptolide in p53 wild-type and p53 mutant ovarian carcinomas
Medical Oncology (2014)
-
MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML
Leukemia (2012)