Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells

Antonella Manca, Maria Cristina Sini, Francesco Izzo, Paolo A. Ascierto, Fabiana Tatangelo, Gerardo Botti, Giusy Gentilcore, Marilena Capone, Nicola Mozzillo, Carla Rozzo, Antonio Cossu, Francesco Tanda, Giuseppe Palmieri

Research output: Contribution to journalArticle

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Abstract

Arginine deiminase (ADI), an arginine-degrading enzyme, has been used in the treatment of tumours sensitive to arginine deprivation, such as malignant melanoma (MM) and hepatocellular carcinoma (HCC). Endogenous production of arginine is mainly dependent on activity of ornithine transcarbamylase (OTC) and argininosuccinate synthetase (ASS) enzymes. We evaluated the effect of ADI treatment on OTC and ASS expression in a series of melanoma cell lines. Twenty-five primary melanoma cell lines and normal fibroblasts as controls underwent cell proliferation assays and Western blot analyses in the presence or absence of ADI. Tissue sections from primary MMs (N=20) and HCCs (N=20) were investigated by immunohistochemistry for ASS expression. Overall, 21/25 (84%) MM cell lines presented a cell growth inhibition by ADI treatment; none of them presented constitutive detectable levels of the ASS protein. However, 7/21 (33%) ADI-sensitive melanoma cell lines presented markedly increased expression levels of the ASS protein following ADI treatment, with a significantly higher IC50 median value. Growth was not inhibited and the IC50 was not reached among the remaining 4/25 (16%) MM cell lines; all of them showed constitutive ASS expression. The OTC protein was found expressed in all melanoma cell lines before and after the ADI treatment Lack of ASS immunostaining was observed in all analyzed in vivo specimens. Our findings suggest that response to ADI treatment in melanoma is significantly correlated with the ability of cells to express ASS either constitutively at basal level (inducing drug resistance) or after the treatment (reducing sensitivity to ADI).

Original languageEnglish
Pages (from-to)1495-1502
Number of pages8
JournalOncology Reports
Volume25
Issue number6
DOIs
Publication statusPublished - 1 Jun 2011
Externally publishedYes

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Ligases
Melanoma
Ornithine Carbamoyltransferase
Cell Line
Arginine
Therapeutics
Inhibitory Concentration 50
Argininosuccinate Synthase
arginine deiminase
Enzymes
Growth
Drug Resistance
Hepatocellular Carcinoma
Proteins
Fibroblasts
Western Blotting
Immunohistochemistry
Cell Proliferation
Neoplasms

Keywords

  • Arginine deiminase
  • Argininosuccinate synthetase
  • Expression analysis
  • In vitro proliferation test
  • Malignant melanoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells. / Manca, Antonella; Sini, Maria Cristina; Izzo, Francesco; Ascierto, Paolo A.; Tatangelo, Fabiana; Botti, Gerardo; Gentilcore, Giusy; Capone, Marilena; Mozzillo, Nicola; Rozzo, Carla; Cossu, Antonio; Tanda, Francesco; Palmieri, Giuseppe.

In: Oncology Reports, Vol. 25, No. 6, 01.06.2011, p. 1495-1502.

Research output: Contribution to journalArticle

Manca, A, Sini, MC, Izzo, F, Ascierto, PA, Tatangelo, F, Botti, G, Gentilcore, G, Capone, M, Mozzillo, N, Rozzo, C, Cossu, A, Tanda, F & Palmieri, G 2011, 'Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells', Oncology Reports, vol. 25, no. 6, pp. 1495-1502. https://doi.org/10.3892/or.2011.1220
Manca, Antonella ; Sini, Maria Cristina ; Izzo, Francesco ; Ascierto, Paolo A. ; Tatangelo, Fabiana ; Botti, Gerardo ; Gentilcore, Giusy ; Capone, Marilena ; Mozzillo, Nicola ; Rozzo, Carla ; Cossu, Antonio ; Tanda, Francesco ; Palmieri, Giuseppe. / Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells. In: Oncology Reports. 2011 ; Vol. 25, No. 6. pp. 1495-1502.
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abstract = "Arginine deiminase (ADI), an arginine-degrading enzyme, has been used in the treatment of tumours sensitive to arginine deprivation, such as malignant melanoma (MM) and hepatocellular carcinoma (HCC). Endogenous production of arginine is mainly dependent on activity of ornithine transcarbamylase (OTC) and argininosuccinate synthetase (ASS) enzymes. We evaluated the effect of ADI treatment on OTC and ASS expression in a series of melanoma cell lines. Twenty-five primary melanoma cell lines and normal fibroblasts as controls underwent cell proliferation assays and Western blot analyses in the presence or absence of ADI. Tissue sections from primary MMs (N=20) and HCCs (N=20) were investigated by immunohistochemistry for ASS expression. Overall, 21/25 (84{\%}) MM cell lines presented a cell growth inhibition by ADI treatment; none of them presented constitutive detectable levels of the ASS protein. However, 7/21 (33{\%}) ADI-sensitive melanoma cell lines presented markedly increased expression levels of the ASS protein following ADI treatment, with a significantly higher IC50 median value. Growth was not inhibited and the IC50 was not reached among the remaining 4/25 (16{\%}) MM cell lines; all of them showed constitutive ASS expression. The OTC protein was found expressed in all melanoma cell lines before and after the ADI treatment Lack of ASS immunostaining was observed in all analyzed in vivo specimens. Our findings suggest that response to ADI treatment in melanoma is significantly correlated with the ability of cells to express ASS either constitutively at basal level (inducing drug resistance) or after the treatment (reducing sensitivity to ADI).",
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AU - Sini, Maria Cristina

AU - Izzo, Francesco

AU - Ascierto, Paolo A.

AU - Tatangelo, Fabiana

AU - Botti, Gerardo

AU - Gentilcore, Giusy

AU - Capone, Marilena

AU - Mozzillo, Nicola

AU - Rozzo, Carla

AU - Cossu, Antonio

AU - Tanda, Francesco

AU - Palmieri, Giuseppe

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