Malignant phenotype of renal cell carcinoma cells is switched by Ukrain administration in vitro

Nicoletta Gagliano, Letizia Pettinari, Massimo Aureli, Carla Martinelli, Elena Colombo, Francesco Costa, Roberta Carminati, Tatiana Volpari, Graziano Colombo, Aldo Milzani, Isabella Dalle-Donne, Magda Gioia

Research output: Contribution to journalArticle

Abstract

We investigated whether Ukrain modulates the malignant phenotype of clear cell renal cell carcinoma (ccRCC) cells Caki-1, Caki-2, and ACHN treated with four doses (5, 10, 20, and 40 μmol/l) for 24 and 48 h. The epithelial-to-mesenchymal transition markers E-cadherin, β-catenin, and vimentin were analyzed by immunofluorescence as well as actin and tubulin; matrix metalloproteinase-2 and matrix metalloproteinase-9 activity was analyzed by SDS-zymography, intracellular and secreted SPARC levels by western blot, and cell cycle by flow cytometry. Ukrain did not induce E-cadherin/β-catenin immunoreactivity at the cell-cell boundary, although it determined the actin cortical expression in Caki-2 and ACHN, and did not affect vimentin organization; however, in some Caki-1 and ACHN cells the perinuclear concentration of vimentin was consistent with its downregulation. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activity was significantly downregulated 48 h after 20 μmol/l Ukrain administration. At this time point, Ukrain significantly decreased migration and invasion, and downregulated SPARC levels in cell supernatants at all doses in Caki-2, and at 20 μmol/l in Caki-1 and ACHN cells. Concomitantly, SPARC was upregulated in all ccRCC cells, suggesting that Ukrain could also affect cell proliferation by cell cycle inhibition, as supported by the cell cycle analysis, as SPARC also acts as a cell cycle inhibitor. Our results suggest that Ukrain may switch the epithelial-to-mesenchymal transition-related phenotype of ccRCC cells, and targets the two major aspects involved in RCC progression, such as tumor invasion/microenvironment remodeling and cell proliferation.

Original languageEnglish
Pages (from-to)749-762
Number of pages14
JournalAnti-Cancer Drugs
Volume22
Issue number8
DOIs
Publication statusPublished - Sep 2011

Keywords

  • cytoskeleton
  • epithelial-to-mesenchymal transition
  • matrix metalloproteinases
  • renal cell carcinoma
  • secreted protein acidic and rich in cysteine
  • tumor invasion

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research
  • Oncology

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  • Cite this

    Gagliano, N., Pettinari, L., Aureli, M., Martinelli, C., Colombo, E., Costa, F., Carminati, R., Volpari, T., Colombo, G., Milzani, A., Dalle-Donne, I., & Gioia, M. (2011). Malignant phenotype of renal cell carcinoma cells is switched by Ukrain administration in vitro. Anti-Cancer Drugs, 22(8), 749-762. https://doi.org/10.1097/CAD.0b013e328346c7f7