Deciphering the role of the mitochondrial chaperonine MCJ in ovarian cancer

Miglietta, Stefano (2021) Deciphering the role of the mitochondrial chaperonine MCJ in ovarian cancer, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare, 33 Ciclo.
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Ovarian cancer (OC) is the most lethal gynecological neoplasm due to its extremely silent invasive capacity, characterized by high mortality frequently caused by therapeutic failure and chemoresistance onset. Recent studies have indicated that the chemotherapy response can be affected by metabolic state and mitochondrial bioenergetic efficiency. Indeed, this latter can finely regulates Wnt/β-catenin pathway which is often involved in OC growth and chemoresistance. Interestingly, the OC therapeutic resistance acquirement has been associated with the silencing of DNAJC15 gene that encodes for the mitochondrial co-chaperonine MCJ, a negative regulator of electron transport chain (ETC) functionality. We therefore hypothesized that MCJ may lead to the re-establishment of pharmacological sensitivity modulating the bioenergetic profile in OC cell models. In this frame, the MCJ overexpression triggers the respiratory capacity and ROS production in OC cells. In addition, we observed an increased cisplatin-sensitivity and lower proliferative and migratory capacities in the MCJ over-expressing chemoresistant cell line. Furthermore, we found that the MCJ over-expression was able to impact on the Wnt/β-catenin signaling pathway, in terms of decreases of β-catenin expression levels accompanied with lower downstream multi-drug resistance and epithelial-mesenchymal transition players in the chemoresistant cells. Based on these data, we speculate that the over-expression of MCJ may modulate the ETC activity and ROS production, inducing β-catenin degradation, which in turn leads to a reduction of both cisplatin-resistance and proliferation of OC chemoresistant cells. The dissection of these mechanisms in which MCJ seems to be involved sets the bases for new insights for this silent killer disease.

Tipologia del documento
Tesi di dottorato
Miglietta, Stefano
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
MCJ, mitochondria, metabolism, ovarian cancer, chemoresistance
Data di discussione
20 Ottobre 2021

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