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RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization

Antonina Germano1, Ida Rapa2, Marco Volante2

  • 1Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.

Molecular and Cellular Endocrinology
|December 16, 2014
PubMed

Insights

Ribonucleotide reductase M1 (RRM1) impacts mitotane metabolism in adrenocortical cancer cells. RRM1 gene up-modulation may cause resistance to mitotane and its metabolites, o,p

Area of Science:

  • Pharmacology
  • Oncology
  • Molecular Biology

Background:

  • Mitotane (o,p'DDD) exhibits anti-proliferative effects in adrenocortical cancer, mediated by its metabolites o,p'DDE and o,p'DDA.
  • A prior study established a link between ribonucleotide reductase M1 (RRM1) expression and o,p'DDD activity, but the underlying mechanism remains unclear.

Purpose of the Study:

  • To investigate the influence of RRM1 on the bioavailability and cytotoxic activity of mitotane and its metabolites (o,p'DDE, o,p'DDA).
  • To explore the role of RRM1 in mitotane resistance mechanisms within adrenocortical cancer cells.

Main Methods:

  • Assessment of mitotane, o,p'DDE, and o,p'DDA cytotoxicity in SW13 and H295R adrenocortical cancer cell lines.
  • Evaluation of RRM1 expression levels in response to drug treatment.
  • Investigation of RRM1 gene silencing effects on intracellular drug metabolism.

Main Results:

  • In H295R cells, mitotane and its metabolites displayed similar cytotoxicity, with no observed impact on RRM1 expression.
  • In SW13 cells, only o,p'DDA showed cytotoxicity without altering RRM1 expression.
  • Lack of sensitivity to o,p'DDE in SW13 cells correlated with RRM1 gene up-modulation, similar to o,p'DDD.
  • RRM1 silencing in SW13 cells enhanced the intracellular conversion of mitotane to o,p'DDE and o,p'DDA.

Conclusions:

  • RRM1 gene expression significantly interferes with mitotane metabolism in adrenocortical cancer cells.
  • RRM1 up-modulation represents a potential mechanism contributing to mitotane drug resistance in this cancer type.
Keywords:
Adrenocortical cancerCell linesMetabolitesMitotaneRRMI

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