The role of gap junction protein Connexin 43 in tumorigenesis of ovarian cancer

Mulchandani, Vaishali (2023) The role of gap junction protein Connexin 43 in tumorigenesis of ovarian cancer. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Vaishali Mulchandani (17IP003)) 17IP003.pdf - Submitted Version Restricted to Repository staff only Download (12MB)

Abstract

Ovarian Cancer, referred to as the silent killer, continues to be the deadliest gynaecological malignancy. The asymptomatic progression of the disease to Stages III and IV necessitates intensive therapy, including debulking surgery coupled with adjuvant radio-chemotherapy. Robust treatment associated with longer radiation cycles and elevated drug concentrations induces toxicity and, eventually death among patients. A better comprehension of the disease progression may pave avenues for curative targeted therapies. The identification of mechanistic markers as novel targets for cancer treatment is a pressing priority at the current time. Connexin 43, pertaining to its conflicting role as a tumour stimulator and a tumour suppressor in different cancers, has been identified as an important target for translational cancer research. This study investigated the nexus between Connexin 43 (Cx43) trafficking and enhanced gap junctional intercellular communication (GJIC) formation in regulating early (ID8) and late-stage (ID8-VEGF) ovarian cancer metastasis and tumorigenesis. The results showed that aggressive tumour-forming ID8-VEGF cell lines had an enhanced expression of intracellular Cx43 as compared to slow tumour-forming ID8 cell lines. Additionally, ID8 cells were capable of minimal GJIC and hemichannel activity, while ID8-VEGF cells were extensively impaired in GJIC and hemichannel activity. Subsequently, the restoration of intercellular communication through the establishment of Tunnelling nanotubes was observed in both cell lines. Furthermore, the administration of 4-Phenylbutyrate (4PBA), an ER stress attenuator, was associated with increased GJIC in ID8 and ID8-VEGF cell lines, perhaps attributed by enhanced Cx43 trafficking to the cell surface. The overexpression of VEGF imparts aggressive tumorigenicity to ID8-VEGF cells as compared to ID8 cells through the modulation of Angiogenesis and Cell motility gene ontology pathways. However, the treatment with 4PBA reverts the modulation of genes in the cell motility gene ontology pathway to restrict ovarian cancer cell migration and tumorigenesis. Thus, indicating the crucial role of gap junction permeability in limiting ovarian cancer tumorigenesis. These findings identify Cx43-GJIC as a potential therapeutic target for the treatment of ovarian cancer in addition to conventional targeted therapies.

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