Differential inactivation of caspase-8 in lung cancers

Narayan Shivapurkar, Shinichi Toyooka, Michael T. Eby, Chun Xian Huang, Ubaradka G. Sathyanarayana, H. Thomas Cunningham, Jyotsna L. Reddy, Elizabeth Brambilla, Takashi Takahashi, John D. Minna, Preet M. Chaudhary, Adi F. Gazdar

Research output: Contribution to journalArticle

Abstract

Caspase-8 (CASP8) is an apoptosis inducing cysteine protease which is activated through the formation of a death-inducing signaling complex when death receptors are complexed to their specific ligands. Recent reports indicate that CASP8 expression is lost via a combination of promoter methylation and allelic loss in a subset of neuroblastomas. We investigated the state of the gene in lung tumors and cell lines. RT-PCR studies indicated that gene expression was lost in most (27 of 34, 79%) of small cell lung carcinoma (SCLC) cell lines, but expression was retained in all 22 non-SCLC (NSCLC) lines tested. Loss of gene expression at the RNA level was associated with absent protein expression by Western blotting and lack of CASP8 enzymatic activity. Methylation of the promoter region of the CASP8 gene was present in 16 of 27 (59%) of the SCLC lines lacking gene expression. All methylated cell lines lacked the presence of an unmethylated allele indicating biallelic methylation or loss of non-methylated allele. Promoter methylation was absent in all SCLC and NSCLC cell lines retaining gene expression, and all of these lines had the unmethylated form of the gene. One non-expressing SCLC cell line, NCI-H82, had a homozygous deletion at 2q33 encompassing the chromosomal location of the CASP8 gene. The mechanism of gene inactivation in the remaining 10 of 27 (37%) non-expressing SCLC cell lines is unknown. Using five polymorphic markers for 2q33 a high frequency of allelic loss was present in SCLC lines. Analyses of fresh tumors showed that 15 of 43 (35%) of the SCLC, seven of 40 (18%) of bronchial carcinoids and none of 44 NSCLC tumors had CASP8 promoter methylation. Because only approximately 60% of SCLC cell lines lacking CASP8 expression were methylated, extrapolating from the cell line data, we estimate that approximately 58% of SCLC and 30% of bronchial carcinoids lack CASP8 expression. Thus, CASP8 expression is absent in a subset of both high grade (SCLC) and low grade (carcinoid) neuroendocrine lung tumors but not in NSCLC, which usually lack neuroendocrine features. CASP8 may function as a tumor suppressor gene in neuroendocrine lung tumors.

Original languageEnglish
Pages (from-to)65-69
Number of pages5
JournalCancer Biology and Therapy
Volume1
Issue number1
DOIs
Publication statusPublished - Jan 2002
Externally publishedYes

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Caspase 8
Lung Neoplasms
Small Cell Lung Carcinoma
Methylation
Cell Line
Non-Small Cell Lung Carcinoma
Carcinoid Tumor
Gene Expression
Neuroendocrine Tumors
Loss of Heterozygosity
Lung
Genes
Death Domain Receptor Signaling Adaptor Proteins
Alleles
Death Domain Receptors
Cysteine Proteases
Gene Silencing
Tumor Cell Line
Tumor Suppressor Genes
Neuroblastoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Shivapurkar, N., Toyooka, S., Eby, M. T., Huang, C. X., Sathyanarayana, U. G., Cunningham, H. T., ... Gazdar, A. F. (2002). Differential inactivation of caspase-8 in lung cancers. Cancer Biology and Therapy, 1(1), 65-69. https://doi.org/10.4161/cbt.1.1.43

Differential inactivation of caspase-8 in lung cancers. / Shivapurkar, Narayan; Toyooka, Shinichi; Eby, Michael T.; Huang, Chun Xian; Sathyanarayana, Ubaradka G.; Cunningham, H. Thomas; Reddy, Jyotsna L.; Brambilla, Elizabeth; Takahashi, Takashi; Minna, John D.; Chaudhary, Preet M.; Gazdar, Adi F.

In: Cancer Biology and Therapy, Vol. 1, No. 1, 01.2002, p. 65-69.

Research output: Contribution to journalArticle

Shivapurkar, N, Toyooka, S, Eby, MT, Huang, CX, Sathyanarayana, UG, Cunningham, HT, Reddy, JL, Brambilla, E, Takahashi, T, Minna, JD, Chaudhary, PM & Gazdar, AF 2002, 'Differential inactivation of caspase-8 in lung cancers', Cancer Biology and Therapy, vol. 1, no. 1, pp. 65-69. https://doi.org/10.4161/cbt.1.1.43
Shivapurkar N, Toyooka S, Eby MT, Huang CX, Sathyanarayana UG, Cunningham HT et al. Differential inactivation of caspase-8 in lung cancers. Cancer Biology and Therapy. 2002 Jan;1(1):65-69. https://doi.org/10.4161/cbt.1.1.43
Shivapurkar, Narayan ; Toyooka, Shinichi ; Eby, Michael T. ; Huang, Chun Xian ; Sathyanarayana, Ubaradka G. ; Cunningham, H. Thomas ; Reddy, Jyotsna L. ; Brambilla, Elizabeth ; Takahashi, Takashi ; Minna, John D. ; Chaudhary, Preet M. ; Gazdar, Adi F. / Differential inactivation of caspase-8 in lung cancers. In: Cancer Biology and Therapy. 2002 ; Vol. 1, No. 1. pp. 65-69.
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