DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress-induced apoptosis

Delia Di Stasi, Viviana Vallacchi, Valentina Campi, Tiziana Ranzani, Maria Daniotti, Elena Chiodini, Silvia Fiorentini, Isabell Greeve, Alessandro Prinetti, Licia Rivoltini, Marco A. Pierotti, Monica Rodolfo

Research output: Contribution to journalArticle

Abstract

The DHCR24 gene encoding for the 3β-hydroxysterol Δ24-reductase, an oxidoreductase involved in cholesterol biosynthesis, was isolated by subtractive hybridization as highly expressed in a short-term melanoma cell line derived from a cutaneous metastases (S/M2) compared to that obtained from the autologous primary tumor (S/P). DHCR24 (alias seladin-1, diminuto/dwarf1 homolog) has been reported to act as an antiapoptotic factor in neurons. Gene expression analysis by Northern blot confirmed that DHCR24 was 5-fold upregulated in S/M2 compared to S/P cells. High levels of DHCR24 gene expression were detected in 13/25 melanoma metastases and in 1/7 primary melanomas by real-time PCR, indicating that upregulation of this gene may occur in melanoma progression. In S/M2 cells, high DHCR24 gene expression associated with resistance to apoptosis triggered by oxidative stress induced by exposure to hydrogen peroxide. DHCR24 gene transfer was shown to protect melanoma cells from H2O2-induced cytotoxicity. Although higher cholesterol levels were shown in S/M2 cells compared to S/P cells, DHCR24 gene transfer did not increase cholesterol content. To evaluate whether DHCR24 acts as an antiapoptotic factor in melanoma metastases, the cytotoxic effect of chemotherapeutic agents was tested in DHCR24 transfectants and in the presence of a DHCR24 inhibitor, U18666A. High DHCR24 gene expression in transfectants did not result in a higher resistance to cytotoxic agents; treatment with U18666A was cytotoxic in S/P cells with a lower DHCR24 content and showed additive cytotoxic effect only when associated with H2O2 and not with cysplatin or etoposide, indicating that the DHCR24 protective effect is exerted through an oxidative stress-specific mechanism.

Original languageEnglish
Pages (from-to)224-230
Number of pages7
JournalInternational Journal of Cancer
Volume115
Issue number2
DOIs
Publication statusPublished - Jun 10 2005

Keywords

  • Cholesterol U18666A
  • DHCR24/seladin-1
  • Melanoma
  • Oxidative stress

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Di Stasi, D., Vallacchi, V., Campi, V., Ranzani, T., Daniotti, M., Chiodini, E., Fiorentini, S., Greeve, I., Prinetti, A., Rivoltini, L., Pierotti, M. A., & Rodolfo, M. (2005). DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress-induced apoptosis. International Journal of Cancer, 115(2), 224-230. https://doi.org/10.1002/ijc.20885