Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer

Vince Kornél Grolmusz, Katalin Karászi, Tamás Micsik, Eszter Angéla Tóth, Katalin Mészáros, Gellért Karvaly, Gábor Barna, Péter Márton Szabó, Kornélia Baghy, János Matkó, Ilona Kovalszky, Miklós Tóth, K. Rácz, Péter Igaz, Attila Patócs

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.

Original languageEnglish
Pages (from-to)2041-2053
Number of pages13
JournalAmerican Journal of Cancer Research
Volume6
Issue number9
Publication statusPublished - 2016

Fingerprint

Adrenal Cortex Neoplasms
gemcitabine
Cell Cycle
Pharmaceutical Preparations
Mitotane
Adrenocortical Adenoma
Ribonucleotides
Ribonucleotide Reductases
Cell Line
cdc Genes
Neoplasms
S Phase
Antineoplastic Agents
Up-Regulation
Biomarkers

Keywords

  • Adrenocortical cancer (ACC)
  • Cell cycle
  • Cell cycle-dependent
  • Chemoresistance
  • Fluorescence activated cell sorting (FACS)
  • Gemcitabine-resistance
  • Malignancy signature
  • Proliferation marker
  • Ribonucleotide reductase
  • Ribonucleotide reductase subunit 2 (RRM2)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Grolmusz, V. K., Karászi, K., Micsik, T., Tóth, E. A., Mészáros, K., Karvaly, G., ... Patócs, A. (2016). Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. American Journal of Cancer Research, 6(9), 2041-2053.

Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. / Grolmusz, Vince Kornél; Karászi, Katalin; Micsik, Tamás; Tóth, Eszter Angéla; Mészáros, Katalin; Karvaly, Gellért; Barna, Gábor; Szabó, Péter Márton; Baghy, Kornélia; Matkó, János; Kovalszky, Ilona; Tóth, Miklós; Rácz, K.; Igaz, Péter; Patócs, Attila.

In: American Journal of Cancer Research, Vol. 6, No. 9, 2016, p. 2041-2053.

Research output: Contribution to journalArticle

Grolmusz, VK, Karászi, K, Micsik, T, Tóth, EA, Mészáros, K, Karvaly, G, Barna, G, Szabó, PM, Baghy, K, Matkó, J, Kovalszky, I, Tóth, M, Rácz, K, Igaz, P & Patócs, A 2016, 'Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer', American Journal of Cancer Research, vol. 6, no. 9, pp. 2041-2053.
Grolmusz VK, Karászi K, Micsik T, Tóth EA, Mészáros K, Karvaly G et al. Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. American Journal of Cancer Research. 2016;6(9):2041-2053.
Grolmusz, Vince Kornél ; Karászi, Katalin ; Micsik, Tamás ; Tóth, Eszter Angéla ; Mészáros, Katalin ; Karvaly, Gellért ; Barna, Gábor ; Szabó, Péter Márton ; Baghy, Kornélia ; Matkó, János ; Kovalszky, Ilona ; Tóth, Miklós ; Rácz, K. ; Igaz, Péter ; Patócs, Attila. / Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. In: American Journal of Cancer Research. 2016 ; Vol. 6, No. 9. pp. 2041-2053.
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