A molecular understanding of d‐homoestrone‐induced G2/M cell cycle arrest in HeLa human cervical carcinoma cells |
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| Authors: | Renáta Minorics Noémi Bózsity Judit Molnár János Wölfling Erzsébet Mernyák Gyula Schneider Imre Ocsovszki István Zupkó |
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| Affiliation: | 1. Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary;2. Department of Organic Chemistry, University of Szeged, Szeged, Hungary;3. Department of Biochemistry, University of Szeged, Szeged, Hungary |
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| Abstract: | 2‐Methoxyestradiol (ME), one of the most widely investigated A‐ring‐modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro‐apoptotic activity, have already been described in detail. The currently tested d ‐ring‐modified analogue of estrone, d ‐homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by d ‐homoestrone in HeLa cells. Apoptosis triggered by d ‐homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase‐8 and ‐9. It was revealed that d ‐homoestrone‐treated HeLa cells are not able to enter mitosis because the cyclin‐dependent kinase 1‐cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2‐ME, d ‐homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the d ‐homoestrone‐triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2‐ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds. |
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| Keywords: | d‐homoestrone tubulin polymerization stathmin loss of function of Cdk1 cell cycle arrest HeLa cells G2/M phase transition Cdc25B and C intrinsic apoptotic pathway |
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