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Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification

Oncogene volume 21, pages 8510–8514 (2002)Cite this article

Abstract

We have previously reported that the key apoptosis related gene caspase 8 (CASP8) is frequently silenced in small cell lung cancer (SCLC) tumors and cell lines usually, but not always, by aberrant promoter methylation. Because CASP8 is a key component of the death-inducing signaling complex (DISC) when specific death receptors (including DR4, DR5, FAS) are activated by their specific ligands (TRAIL/FASL), we examined expression of the components of the DISC complex in lung cancer cell lines. MYC family members are frequently amplified (MYC+ve) in SCLC, and MYC is a potent inducer of apoptosis. We examined 34 SCLC lines (12 of which were MYC+ve) and 22 NSCLC lines. CASP8 gene expression was frequently lost (79%) at message and protein levels in SCLC but not in non-SCLC (NSCLC). MYC amplification was present in 45% of SCLC cell lines, which had lost CASP8 expression, but not in any of the CASP8 positive lines. The frequency of CASP8 loss was significantly higher in MYC+ve SCLC compared to MYC−ve SCLC or in NSCLC. Analyses of other DISC components showed significantly higher rates of loss of expression of CASP10, DR5, FAS and FASL in SCLC compared to NSCLC. The loss of expression of proapoptotic DISC components was significantly higher in MYC+ve SCLC cell lines and these lines were completely resistant to TRAIL. Expression of CASP10 (a caspase closely related to CASP8) was frequently absent at the protein level in both SCLC and NSCLC lines. Expression of c-FLIP (proteolytically inactive homolog of CASP8) was inversely related to expression of CASP8. Our major conclusions are: (a) The death receptor pathway is differently inactivated at multiple levels in lung cancer cell lines; and (b) MYC amplification in SCLC is associated with inactivation of most components of the DISC complex, with resistance to TRAIL and with expression of c-FLIP. These findings may have considerable clinical and therapeutic implications.

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Abbreviations

SCLC:

small cell carcinoma

NSCLC:

non small cell carcinoma

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Acknowledgements

Supported by a Specialized Program of Research Excellence (SPORE) grant, P50-CA70907 from the National Cancer Institute, Bethesda, MD, USA (to AF Gazdar) and a grant, AI/AR47230-01 from the National Institute of Allergy and Infectious Diseases (to PM Chaudhary).

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Authors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, Dallas, 75390-8593, Texas, TX, USA

    Narayan Shivapurkar, Jyotsna Reddy, Hittu Matta, Ubaradka G Sathyanarayana, C X Huang, Shinichi Toyooka, John D Minna, Preet M Chaudhary & Adi F Gazdar

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, 75235, Texas, TX, USA

    Narayan Shivapurkar, Ubaradka G Sathyanarayana & Adi F Gazdar

  3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75235, Texas, TX, USA

    John D Minna & Preet M Chaudhary

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  1. Narayan Shivapurkar
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  9. Adi F Gazdar
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Correspondence to Adi F Gazdar.

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Shivapurkar, N., Reddy, J., Matta, H. et al. Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification. Oncogene 21, 8510–8514 (2002). https://doi.org/10.1038/sj.onc.1205941

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