RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization. (5th February 2015)

• Record Type: Journal Article
• Authors: Germano, Antonina; Rapa, Ida; Volante, Marco; De Francia, Silvia; Migliore, Cristina; Berruti, Alfredo; Papotti, Mauro; Terzolo, Massimo
• Is Part Of: Molecular and cellular endocrinology. Volume 401(2015)
• Page Start: 105
• Page End: 110
• Publication Date: 2015-02-05
• Subjects: RRMI -- Mitotane -- Metabolites -- Adrenocortical cancer -- Cell lines; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2014.11.027
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: Mitotane metabolites have cell type-specific anti-proliferative effects. Responsiveness to mitotane metabolites is associated to modulation of RRM1 expression. RRM1 directly interferes with mitotane intracellular metabolization. Abstract: The anti-proliferative activity of mitotane (o, p′DDD) in adrenocortical cancer is mediated by its metabolites o, p′DDE and o, p′DDA. We previously demonstrated a functional link between ribonucleotide reductase M1(RRM1) expression and o, p′DDD activity, but the mechanism is unknown. In this study we assessed the impact of RRM1 on the bioavailability and cytotoxic activity of o, p′DDD, o, p′DDE and o, p′DDA in SW13 and H295R cells. In H295R cells, mitotane and its metabolites showed a similar cytotoxicity and RRM1 expression was not influenced by any drug. In SW13 cells, o, p′DDA only showed a cytotoxic activity and did not modify RRM1 expression, whereas the lack of sensitivity to o, p′DDE was associated to RRM1 gene up-modulation, as already demonstrated for o, p′DDD. RRM1 silencing in SW13 cells increased the intracellular transformation of mitotane into o, p′DDE and o, p′DDA. These data demonstrate that RRM1 gene interferes with mitotane metabolism in adrenocortical cancer cells, as a possible mechanisms of drug resistance.