Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re‐expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3‐{[2‐chloro‐1‐(4‐chlorobenzyl)‐5‐methoxy‐6-methyl‐1H‐indol‐3‐yl]methylene}‐5‐hydroxy‐6‐methyl‐1,3‐dihydro‐2H‐indol‐2‐one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti‐carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ERβ. Mass spectrometry‐based approaches were used to analyze histone post‐translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ERβ/3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects.
Indole derivative interacts with estrogen receptor beta and inhibits human ovarian cancer cell growth / Verardi L.; Fiori J.; Andrisano V.; Locatelli A.; Morigi R.; Naldi M.; Bertucci C.; Strocchi E.; Boga C.; Micheletti G.; Calonghi N.. - In: MOLECULES. - ISSN 1420-3049. - ELETTRONICO. - 25:19(2020), pp. 4438.1-4438.15. [10.3390/molecules25194438]
Indole derivative interacts with estrogen receptor beta and inhibits human ovarian cancer cell growth
Fiori J.Investigation
;Andrisano V.Membro del Collaboration Group
;Locatelli A.Membro del Collaboration Group
;Morigi R.Investigation
;Naldi M.Investigation
;Bertucci C.Membro del Collaboration Group
;Boga C.
Writing – Review & Editing
;Micheletti G.Membro del Collaboration Group
;Calonghi N.
Conceptualization
2020
Abstract
Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re‐expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3‐{[2‐chloro‐1‐(4‐chlorobenzyl)‐5‐methoxy‐6-methyl‐1H‐indol‐3‐yl]methylene}‐5‐hydroxy‐6‐methyl‐1,3‐dihydro‐2H‐indol‐2‐one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti‐carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ERβ. Mass spectrometry‐based approaches were used to analyze histone post‐translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ERβ/3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects.File | Dimensione | Formato | |
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