Pharmacological inhibition of protein kinase D2/Aurora kinase A signalling axis suppresses G2/M cell cycle progression and proliferation of epithelial ovarian cancer cells.
Pathol Res Pract
; 260: 155390, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38878668
ABSTRACT
Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy with poor prognosis and patient survival outcome. Protein kinase D2 (PKD2) belongs to Ca++/calmodulin-dependent serine/threonine kinase family and its aberrant expression is associated with many cellular and physiological functions associated with tumorigenesis including cell proliferation. We show that PKD2 is activated during G2/M cell cycle transition and its catalytic inactivation by small molecule inhibitor CRT0066101 or genetic knockdown caused suppression of EOC cell proliferation followed by a delay into mitotic entry. Our RNASeq analysis of PKD2-inactivated EOC cells revealed significant downregulation of genes associated with cell cycle including Aurora kinase A, a critical mitotic regulator. Mechanistically, PKD2 positively regulated Aurora kinase A stability at both transcriptional and post-translational levels by interfering with the function of Fbxw7, drove G2/M cell cycle transition and EOC cell proliferation. Moreover, pharmacological inhibition of Aurora kinase A by small molecule CD532 or its shRNA-mediated genetic knockdown suppressed EOC cell proliferation, induced G2/M cell cycle arrest and mitotic catastrophe followed by apoptosis. Taken together, our results indicated that PKD2 positively regulates Aurora kinase A during G2/M cell cycle entry and pharmacological targeting of PKD2/Aurora kinase A signalling axis could serve as a novel therapeutic intervention against a lethal pathology like EOC.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
/
Transducción de Señal
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Proliferación Celular
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Aurora Quinasa A
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Carcinoma Epitelial de Ovario
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Proteína Quinasa D2
Límite:
Female
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Humans
Idioma:
En
Revista:
Pathol Res Pract
Año:
2024
Tipo del documento:
Article