Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma

Our plain-English summary of Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma, by G.J. Gordon, K. Appasani, J.P. Parcells, et al (Carcinogenesis, 2002).

The study

• Authors: G.J. Gordon, K. Appasani, J.P. Parcells, N.K. Mukhopadhyay, M.T. Jaklitsch, W.G. Richards, D.J. Sugarbaker, R. Bueno
• Journal: Carcinogenesis
• Published: 2002;23(6):1017-24
• Cited by: 56 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a highly lethal pleural neoplasm that is often resistant to chemotherapeutic drugs, including cisplatin, and for which little is known regarding carcinogenic pathways. We used differential display to compare gene expression patterns in mesothelioma, normal pleura and normal lung, in order to better understand MPM pathobiology, and to search for genes that may facilitate drug resistance in this cancer. The human inhibitor of apoptosis protein-1 gene (IAP-1/MIHC/cIAP2) was discovered to be highly expressed in MPM. We confirmed overexpression of IAP-1 mRNA and protein in 39 additional human MPM tumor specimens and 3/5 (60%) MPM cell lines by multiple methods, including real time quantitative reverse transcription-PCR and western blot analysis. Using an antisense targeting approach, we found that attenuation of IAP-1 mRNA levels decreases baseline cell viability and increases the sensitivity of MPM cell lines to cisplatin by nearly 20-fold. Reduced IAP-1 gene expression also results in a concordant increase of the pro-apoptotic cleavage product of caspase 9 and a reduction in the number of viable tumor cells. Our observations strongly suggest that IAP-1 is at least partly responsible for promoting carcinogenesis and mediating resistance to cisplatin in many MPM tumors and that further study of this apoptotic pathway is warranted.

In plain English

This was a laboratory study of tumor tissue and cells. The study did not report any analysis of asbestos exposure. The authors compared gene activity in surgical samples of malignant pleural mesothelioma, normal lung and normal pleura from Brigham and Women's Hospital. They focused on a gene called inhibitor of apoptosis protein-1 (IAP-1), which helps cells avoid self-destruction. IAP-1 messenger RNA was found in all 39 mesothelioma samples tested. Its median level was 90 times higher (range 2.5 to 1000 times) than the average level in three normal pleura samples. This increase was higher in epithelial tumors (181-fold) than in non-epithelial tumors (64-fold). The authors found no significant link between IAP-1 levels and patient survival. Three of five mesothelioma cell lines had significantly higher IAP-1 messenger RNA levels than normal pleura. When the authors lowered IAP-1 in one cell line, the cisplatin dose needed to kill half the cells fell about 20-fold. A marker of cell self-destruction also appeared even without the drug. The authors concluded that IAP-1 plays some role in many mesothelioma tumors and in their resistance to cisplatin.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human tumor and normal tissue specimens and mesothelioma cell lines, including gene-expression comparisons and an antisense experiment that reduced IAP-1 in one cell line
• Who was studied: Surgical specimens of malignant pleural mesothelioma, normal lung and normal pleura came from patients having thoracic surgery at Brigham and Women's Hospital (Boston) who had no treatment before surgery. They included 39 mesothelioma samples measured for IAP-1 messenger RNA, compared with normal pleura samples. The study also used five established mesothelioma cell lines and two lung cancer cell lines as controls. No dates were given.
• Exposure: No analysis of asbestos exposure was reported. In the cell experiments, mesothelioma cell lines were exposed to the chemotherapy drug cisplatin at 2 to 250 µM for 1 hour.
• Main results:
  • IAP-1 mRNA was detected in all 39 mesothelioma tumor samples. Its median level was 90 times higher (range 2.5–1000-fold) than the average IAP-1 mRNA level in normal pleura samples.
  • The normal pleura specimens examined numbered three.
  • The median increase in IAP-1 mRNA was 181-fold in epithelial subtype tumors. This was significantly higher than the 64-fold increase in non-epithelial tumors.
  • The authors found no significant correlation between IAP-1 levels in the tumor samples and patient survival.
  • IAP-1 mRNA was expressed at significantly higher levels than in normal pleura in 3 of 5 (60%) mesothelioma cell lines. IAP-1 protein was detected in all five cell lines.
  • On average, the cell line with the most IAP-1 mRNA (94-589) was almost four times as resistant to cisplatin as the cell lines with the least IAP-1 mRNA.
  • IAP-1 was reduced in 94-589 cells using an antisense vector. In these cells, the cisplatin dose needed to kill half the cells (IC50) fell about 20-fold compared with the parent cells.
  • In the IAP-1 antisense cell line, the cleavage fragment of caspase 9 (linked to cell self-destruction) was present even without cisplatin. It peaked 1 hour after cisplatin exposure.
  • In all mesothelioma tumors studied, stromal cells (the non-tumor supporting tissue) showed no detectable IAP-1 protein.
• The authors' conclusion: The authors concluded that their results strongly suggest that IAP-1 and related apoptosis pathways play some role in the development of many malignant pleural mesothelioma tumors. They also concluded that these pathways contribute to the cancer's drug resistance.
• Limitations the authors state:
  • The tumor specimens were not standardized to clinical factors such as stage or treatment. The authors gave this as the reason no link with survival was found.
  • IAP-1 levels were compared with normal pleura tissue because normal mesothelial cells cannot be grown long-term in culture.
  • The stable antisense cell lines were, by definition, a subset of cells able to survive with the antisense construct.
  • It is not known whether IAP-1 interacts with other caspases in mesothelioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelioma, Pleural Mesothelioma, Neoplasm, Cisplatin, Carcinogenic, Pleura, Carcinogenesis.

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