Parisa Esmaeili (Lund / SE), Fredrik Levander (Lund / SE), Kazi Uddin (Lund / SE), Ahmad Nasimian (Lund / SE), Anna Sandström Gerdtsson (Lund / SE), Sergio Mosquim Junior (Lund / SE)
High-grade serous ovarian carcinoma (HGSOC) is the most lethal form of ovarian cancer, accounting for the majority of ovarian cancer-related deaths. It typically presents at advanced stages, often with metastasis, complicating treatment efforts. Despite an initial response to chemotherapy, resistance frequently develops, emphasizing the need for new therapeutic strategies. Identifying signature proteins that could serve as potential drug targets for overcoming resistance in metastasized high-grade ovarian cancer would be of immense value in addressing this challenge.
In this study, we investigated the interaction between MTDH and SND1, both of which have been shown to be overexpressed in various types of cancer by others and us. We aimed to examine their roles and potential as therapeutic targets in ovarian cancer.
We performed comprehensive proteomics and phosphoproteomics using cell line models to investigate the changes resulting from the inhibition of MTDH-SND1 interaction. Additionally, we conducted proteomics and phosphoproteomics on cells with silenced MTDH or SND1 to observe the effects of gene silencing, allowing us to compare these effects with those observed from direct inhibition. The data were analysed using enrichment analysis of gene ontologies and pathways to gain insights into the underlying biological processes and pathways involved.
Inhibiting the MTDH and SND1 interaction resulted in a reduction in cell growth and motility-related pathways, as well as in the molecular functions of the cancer cells. These effects were comparable to those observed when the target genes were silenced. This similarity suggests that both inhibition and silencing of the drug targets disrupt pathways and molecular functions necessary for cancer cell proliferation and progression. Additionally, we observed a significant reduction in cell viability in cisplatin-resistant cells in both monolayer and spheroid models when the interaction between the drug targets was blocked. This finding highlights the potential of targeting the MTDH-SND1 interaction to overcome chemoresistance and improve therapeutic outcomes in ovarian cancer.
Furthermore, the study underscores the crucial role of proteomic and phosphoproteomic analyses in identifying, characterizing, and validating novel therapeutic targets for effective treatment strategies in ovarian cancer.