This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ferreira, C. G. Articles by Giaccone, G. Search for Related Content PubMed PubMed Citation Articles by Ferreira, C. G. Articles by Giaccone, G.

Chemotherapy Triggers Apoptosis in a Caspase-8-dependent and Mitochondria-controlled Manner in the Non-Small Cell Lung Cancer Cell Line NCI-H460

Department of Medical Oncology, Academic Hospital Vrije Universiteit Amsterdam, 1081HV Amsterdam, the Netherlands

Chemotherapy-induced apoptosis is generally thought to be dependent on a pathway headed by caspase-9. This model is primarily based on studies performed in leukemia cells; however, little is known about caspase cascades in relatively resistant solid tumor cells, including non-small cell lung cancer (NSCLC) cells. Using the NSCLC cell line NCI-H460 (H460), here, we studied the effect of stable expression of various caspase inhibitors on apoptosis induced by the anticancer drugs cisplatin, topotecan, and gemcitabine. Interestingly, overexpression of caspase-9S and X-linked inhibitor of apoptosis (XIAP), both able to inhibit caspase-9 activity, failed to block apoptosis. In contrast, stable expression of caspase-8 inhibitors, such as cytokine response modifier A (CrmA) and dominant-negative caspase-8, almost completely abrogated apoptosis and also enhanced clonogenic survival. Caspase-8 activation in H460 cells was not mediated by death receptors, inasmuch as overexpression of dominant-negative Fas-associated death domain (FADD-DN) did not prevent procaspase-8 cleavage and subsequent apoptosis. However, stable expression of Bcl-2 and Bcl-x_L did suppress these apoptotic events, including the release of cytochrome c from mitochondria, which was observed in drug-treated H460 cells. In the NSCLC cell line H460, we, thus, provide evidence for the existence of a novel drug-inducible apoptotic pathway in which activation of caspase-8, and not of caspase-9, forms the apical and mitochondria-dependent step that subsequently activates the downstream caspases.

This article has been cited by other articles:

				T. Yeo, J Kintner, R Armand, R Perez, and L. Lewis Sublethal concentrations of gemcitabine (2',2'-difluorodeoxycytidine) alter mitochondrial ultrastructure and function without reducing mitochondrial DNA content in BxPC-3 human pancreatic carcinoma cells Human and Experimental Toxicology, December 1, 2007; 26(12): 911 - 921. [Abstract] [PDF]

				J.-S. Kim, Y.-C. Lee, H.-T. Nam, G. Li, E.-J. Yun, K.-S. Song, K.-S. Seo, J.-H. Park, J.-W. Ahn, O. Zee, et al. Apicularen A Induces Cell Death through Fas Ligand Up-Regulation and Microtubule Disruption by Tubulin Down-Regulation in HM7 Human Colon Cancer Cells Clin. Cancer Res., November 1, 2007; 13(21): 6509 - 6517. [Abstract] [Full Text] [PDF]

				J. Voortman, T. P. Resende, M. A.I. Abou El Hassan, G. Giaccone, and F. A.E. Kruyt TRAIL therapy in non-small cell lung cancer cells: sensitization to death receptor-mediated apoptosis by proteasome inhibitor bortezomib Mol. Cancer Ther., July 1, 2007; 6(7): 2103 - 2112. [Abstract] [Full Text] [PDF]

				J. Voortman, A. Checinska, G. Giaccone, J. A. Rodriguez, and F. A.E. Kruyt Bortezomib, but not cisplatin, induces mitochondria-dependent apoptosis accompanied by up-regulation of noxa in the non-small cell lung cancer cell line NCI-H460 Mol. Cancer Ther., March 1, 2007; 6(3): 1046 - 1053. [Abstract] [Full Text] [PDF]

				W. S. Tsai, W.-S. Yeow, A. Chua, R. M. Reddy, D. M. Nguyen, D. S. Schrump, and D. M. Nguyen Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin Mol. Cancer Ther., December 1, 2006; 5(12): 2977 - 2990. [Abstract] [Full Text] [PDF]

				S. Xia, E. M. Rosen, and J. Laterra Sensitization of Glioma Cells to Fas-Dependent Apoptosis by Chemotherapy-Induced Oxidative Stress Cancer Res., June 15, 2005; 65(12): 5248 - 5255. [Abstract] [Full Text] [PDF]

				D. A. Fennell Caspase Regulation in Non-Small Cell Lung Cancer and its Potential for Therapeutic Exploitation Clin. Cancer Res., March 15, 2005; 11(6): 2097 - 2105. [Abstract] [Full Text] [PDF]

				B. Pauwels, A. E.C. Korst, F. Lardon, and J. B. Vermorken Combined Modality Therapy of Gemcitabine and Radiation Oncologist, January 1, 2005; 10(1): 34 - 51. [Abstract] [Full Text] [PDF]

				S.-J. Park, C.-H. Wu, J. D. Gordon, X. Zhong, A. Emami, and A. R. Safa Taxol Induces Caspase-10-dependent Apoptosis J. Biol. Chem., December 3, 2004; 279(49): 51057 - 51067. [Abstract] [Full Text] [PDF]

				M. A. I. Abou El Hassan, I. van der Meulen-Muileman, S. Abbas, and F. A. E. Kruyt Conditionally Replicating Adenoviruses Kill Tumor Cells via a Basic Apoptotic Machinery-Independent Mechanism That Resembles Necrosis-Like Programmed Cell Death J. Virol., November 15, 2004; 78(22): 12243 - 12251. [Abstract] [Full Text] [PDF]

				J. C. Wilkinson, E. Cepero, L. H. Boise, and C. S. Duckett Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis Mol. Cell. Biol., August 15, 2004; 24(16): 7003 - 7014. [Abstract] [Full Text] [PDF]

				C. Ruiz-Ruiz, C. Ruiz de Almodovar, A. Rodriguez, G. Ortiz-Ferron, J. M. Redondo, and A. Lopez-Rivas The Up-regulation of Human Caspase-8 by Interferon-{gamma} in Breast Tumor Cells Requires the Induction and Action of the Transcription Factor Interferon Regulatory Factor-1 J. Biol. Chem., May 7, 2004; 279(19): 19712 - 19720. [Abstract] [Full Text] [PDF]

				L. E. Broker, C. Huisman, S. W. Span, J. A. Rodriguez, F. A. E. Kruyt, and G. Giaccone Cathepsin B Mediates Caspase-Independent Cell Death Induced by Microtubule Stabilizing Agents in Non-Small Cell Lung Cancer Cells Cancer Res., January 1, 2004; 64(1): 27 - 30. [Abstract] [Full Text] [PDF]

				F. A. E. Kruyt, A. Checinska, G. Giaccone, and C. G. Ferreira Correspondence re: L. Yang et al., Predominant Suppression of Apoptosome by Inhibitor of Apoptosis Protein in Non-Small Cell Lung Cancer H460 Cells: Therapeutic Effect of a Novel Polyarginine-conjugated Smac Peptide. Cancer Res., 63: 831-837, 2003. Cancer Res., October 1, 2003; 63(19): 6566 - 6567. [Full Text] [PDF]

				T. Mashima, L. Yang, and T. Tsuruo Reply Cancer Res., October 1, 2003; 63(19): 6568 - 6568. [Full Text] [PDF]

				J. H. Song, D. K. Song, M. Herlyn, K. C. Petruk, and C. Hao Cisplatin Down-Regulation of Cellular Fas-associated Death Domain-like Interleukin-1{beta}-converting Enzyme-like Inhibitory Proteins to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Melanoma Cells Clin. Cancer Res., September 15, 2003; 9(11): 4255 - 4266. [Abstract] [Full Text] [PDF]

				D. C. J. Spierings, E. G. E. de Vries, W. Timens, H. J. M. Groen, H. M. Boezen, and S. de Jong Expression of TRAIL and TRAIL Death Receptors in Stage III Non-Small Cell Lung Cancer Tumors Clin. Cancer Res., August 1, 2003; 9(9): 3397 - 3405. [Abstract] [Full Text] [PDF]

				R. Danesi, F. De Braud, S. Fogli, T. M. De Pas, A. Di Paolo, G. Curigliano, and M. Del Tacca Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer Pharmacol. Rev., March 1, 2003; 55(1): 57 - 103. [Abstract] [Full Text] [PDF]

				T. Mueller, W. Voigt, H. Simon, A. Fruehauf, A. Bulankin, A. Grothey, and H.-J. Schmoll Failure of Activation of Caspase-9 Induces a Higher Threshold for Apoptosis and Cisplatin Resistance in Testicular Cancer Cancer Res., January 15, 2003; 63(2): 513 - 521. [Abstract] [Full Text] [PDF]

				J.-i. Sasaki, R. Ramesh, S. Chada, Y. Gomyo, J. A. Roth, and T. Mukhopadhyay The Anthelmintic Drug Mebendazole Induces Mitotic Arrest and Apoptosis by Depolymerizing Tubulin in Non-Small Cell Lung Cancer Cells Mol. Cancer Ther., November 1, 2002; 1(13): 1201 - 1209. [Abstract] [Full Text] [PDF]

				L. E. Broker, C. Huisman, C. G. Ferreira, J. A. Rodriguez, F. A. E. Kruyt, and G. Giaccone Late Activation of Apoptotic Pathways Plays a Negligible Role in Mediating the Cytotoxic Effects of Discodermolide and Epothilone B in Non-Small Cell Lung Cancer Cells Cancer Res., July 15, 2002; 62(14): 4081 - 4088. [Abstract] [Full Text] [PDF]

				D. R. Jones, R. M. Broad, L. D. Comeau, S. J. Parsons, and M. W. Mayo Inhibition of nuclear factor {kappa}B chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation J. Thorac. Cardiovasc. Surg., February 1, 2002; 123(2): 310 - 317. [Abstract] [Full Text] [PDF]

				C. Huisman, C. G. Ferreira, L. E. Broker, J. A. Rodriguez, E. F. Smit, P. E. Postmus, F. A. E. Kruyt, and G. Giaccone Paclitaxel Triggers Cell Death Primarily via Caspase-independent Routes in the Non-Small Cell Lung Cancer Cell Line NCI-H460 Clin. Cancer Res., February 1, 2002; 8(2): 596 - 606. [Abstract] [Full Text] [PDF]

				D. T. Jones, K. Ganeshaguru, A. E. Virchis, N. I. Folarin, M. W. Lowdell, A. B. Mehta, H. G. Prentice, A. V. Hoffbrand, and R. G. Wickremasinghe Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation Blood, November 1, 2001; 98(9): 2800 - 2807. [Abstract] [Full Text] [PDF]

				C. G. Ferreira, P. van der Valk, S. W. Span, I. Ludwig, E. F. Smit, F. A. E. Kruyt, H. M. Pinedo, H. van Tinteren, and G. Giaccone Expression of X-linked Inhibitor of Apoptosis as a Novel Prognostic Marker in Radically Resected Non-Small Cell Lung Cancer Patients Clin. Cancer Res., August 1, 2001; 7(8): 2468 - 2474. [Abstract] [Full Text] [PDF]