Placenta growth factor induces melanoma resistance to temozolomide through a mechanism that involves the activation of the transcription factor NF-κB

Lauretta Levati, Federica Ruffini, Alessia Muzi, Kazuo Umezawa, Grazia Graziani, Stefania D'Atri, Pedro Miguel Lacal

Research output: Contribution to journalArticlepeer-review

Abstract

Placenta growth factor (PlGF) and its receptor vascular endothelial growth factor receptor-1 (VEGFR-1) are co-expressed in a large number of human melanoma cell lines. Moreover, a correlation between in vivo PlGF production and melanoma progression has been suggested. To investigate whether PlGF might have a role in protecting melanoma cells from the cytotoxic effects of the anticancer agent temozolomide (TMZ), which is used for the treatment of this malignancy, we stably transfected a doxycycline-inducible PlGF antisense mRNA into a human melanoma cell clone that secretes VEGF-A and PlGF and expresses receptors for both growth factors. Induction of PlGF antisense mRNA in the transfected cells (13443/ASP3 subclone) halved TMZ IC50, and exogenous addition of PlGF to the culture medium 24 h before TMZ treatment, partially restored IC 50 values to that of control cells. The increased sensitivity of 13443/ASP3 cells upon PlGF antisense mRNA expression was not due to down-regulation of O6-methylguanine-DNA methyltransferase, a DNA repair protein that represents the main mechanism of resistance to TMZ. Since the activity of the transcription factor nuclear factor-κB (NF-κB) has been correlated to melanoma chemoresistance, we investigated whether NF-κB was involved in PlGF-induced melanoma cell resistance to TMZ. Induction of PlGF antisense mRNA in 13443/ASP3 cells halved the levels of active NF-κB and the specific inhibition of this transcription factor increased sensitivity of 13443/ASP3 cells to TMZ. In conclusion, our data strongly suggest that PlGF plays a role in melanoma cell resistance to TMZ through a pathway that involves NF-κB activation.

Original languageEnglish
Pages (from-to)241-247
Number of pages7
JournalInternational Journal of Oncology
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Melanoma
  • NF-κB
  • PlGF
  • Temozolomide resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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