Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype

Our plain-English summary of Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype, by S. Apostolou, J.O. Klein, Y. Mitsuuchi, et al (Oncogene, 2004).

The study

• Authors: S. Apostolou, J.O. Klein, Y. Mitsuuchi, J.N. Shetler, P.I. Poulikakos, S.C. Jhanwar, W.D. Kruger, J.R. Testa
• Journal: Oncogene
• Published: 2004;23(29):5032-40
• Cited by: 65 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesotheliomas (MMs) are aggressive tumors derived from mesothelial cells lining the lungs, pericardium and peritoneum, and are often associated with occupational asbestos exposure. Suppression subtractive hybridization was used to identify genes differentially expressed in MM cells compared to normal mesothelial cells. A gene, SEP15, encoding a 15-kDa selenium-containing protein was isolated using this approach and was subsequently shown to be downregulated in approximately 60% of MM cell lines and tumor specimens. A SEP15 polymorphic variant, 1125A, resides in the SECIS recognition element in the 3'-UTR and may influence the efficiency of Sec incorporation into the protein during translation. Since previous studies have implicated a potential role of the trace element selenium as a chemopreventive agent in animal models and in several types of human cancer, we investigated the effect of selenium on MM cells and its dependence on SEP15 genotype. Selenium was shown to inhibit cell growth and induce apoptosis in a dose-dependent manner in MM cells but had minimal effect on normal mesothelial cells. However, MM cells with downregulated SEP15 or the 1125A variant were somewhat less responsive to the growth inhibitory and apoptotic effects of selenium than MM cells expressing wild-type protein. RNAi-based knockdown studies demonstrated that SEP15 inhibition makes sensitive MM cells more resistant to selenium. These data imply that selenium may be useful as a chemopreventive agent in individuals at high risk of MM due to asbestos exposure, although those with the 1125A polymorphism may be less responsive to the protective benefits of dietary selenium supplementation.

In plain English

This laboratory study used mesothelioma cells grown in culture, not people exposed to asbestos. SEP15, the gene for a selenium-containing protein, was expressed at least two-fold lower than in normal mesothelial cells in 14 of 23 (60%) mesothelioma cell lines. It was also lower in three of five tumor specimens. Adding selenium as selenocysteine slowed the growth of all seven mesothelioma cell lines tested but had little or no effect on normal mesothelial cells. Lines with the usual (wild-type) SEP15 responded most. Lines with a gene variant called 1125A, or with reduced SEP15, responded less, both in growth and in programmed cell death (apoptosis). Reducing SEP15 in a sensitive line made it less responsive. The variant's distribution did not differ statistically significantly between blood from 36 mesothelioma patients and 48 people from the general population. The authors concluded that, if confirmed in a living-animal model, the findings may provide a rationale for possibly using selenium as a preventive agent in asbestos workers. They noted that tumor samples were too few for firm conclusions and the genotype sample was small.

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 (in vitro) study of mesothelioma and normal mesothelial cells in culture, with gene expression, gene knockdown and transfection experiments, plus a comparison of SEP15 genotype frequencies
• Who was studied: Human malignant mesothelioma (MM) cell lines and tumor specimens, and normal human mesothelial cell cultures. Gene expression was measured in 23 MM cell lines and 5 tumor specimens, and selenium was tested on 7 MM cell lines and 1 normal culture. Genotype was determined in 60 MM tumors/cell lines, blood from 36 MM cases and 48 people from the general population. The article does not state where or when the samples were collected.
• Exposure: Selenium added to the culture medium in three chemical forms: selenomethionine, sodium selenite and selenocysteine. Asbestos exposure was not studied.
• Main results:
  • SEP15 expression was downregulated two-fold or more in 14 of 23 (60%) MM cell lines, compared with normal mesothelial cells.
  • SEP15 expression was downregulated in three of five MM tumor specimens, compared with normal mesothelial cells. No fold threshold is stated for the tumors.
  • Selenocysteine inhibited growth in all MM cell lines tested but had little or no effect on normal mesothelial cells. Inhibition was most pronounced in lines with wild-type SEP15, less in lines with the 1125A variant, and least in lines with reduced SEP15.
  • With sodium selenite, apoptosis was much higher in an MM line with wild-type SEP15 (Meso 59) than in lines with downregulated SEP15 (Meso 8) or the 1125A variant (Meso 34). Selenium induced only low levels of apoptosis in normal mesothelial cells.
  • In Meso 8 cells given SEP15 genes, the higher selenocysteine concentration left about 16% of cells apoptotic among those given wild-type SEP15, versus 4–6% among those given the 1125A variant.
  • When SEP15 was reduced by siRNA in the sensitive Meso 6 line, the cells proliferated more after selenium exposure and showed less apoptosis after selenocysteine treatment.
  • SEP15 1125 genotypes (G, G/A, A) were 46%, 50% and 4% in the general population (n = 48) and 39%, 61% and 0% in blood from MM cases (n = 36). The difference in allele distribution was not statistically significant.
  • No mutations were found in the coding region of SEP15 in 20 MM cell lines with loss of heterozygosity at 1p31.
• The authors' conclusion: The authors concluded that, if their in vitro findings are confirmed in an in vivo model, they may provide a rationale for the possibility of using selenium as a chemopreventive agent in asbestos workers or other occupationally exposed groups at high risk of mesothelioma. They added that SEP15 genotyping might help identify who is more likely to benefit.
• Limitations the authors state:
  • The number of tumor samples was too few to draw firm conclusions about SEP15 expression in primary tumors.
  • Other unknown genetic differences among the MM cell lines might influence selenium sensitivity and SEP15 expression.
  • The sample size for the genotype comparison was small.

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, Mesothelial Cells, Pericardium, Peritoneum, Asbestos Exposure.

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• Increased urinary 8-isoprostaglandin F(2)alpha is associated with lower plasma selenium levels and lower vegetable and fruit intake in an asbestos-exposed cohort at risk for lung cancer — E.B. Gottschall, P. Wolfe, et al. (2004)
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• Novel cell imaging techniques show induction of apoptosis and proliferation in mesothelial cells by asbestos — J.L. Goldberg, C.L. Zanella, et al. (1997)
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