| الوصف: |
CIB1 is a viable cancer target and depleting CIB1 causes selective cancer cell death. My thesis work focuses on understanding the cell death mechanisms upon CIB1 depletion. In this study, we explore the effects of depleting CIB1 in triple-negative breast cancer (TNBC) cells in combination with chemotherapy and determined the underlying mechanisms behind the specific killing of cancer cells. TNBC is defined by a lack of targetable cell surface receptors – estrogen, progesterone, and HER2. To date, no targeted therapies are clinically approved; the standard of care for TNBC patients is limited to surgery and chemotherapy. Here, we introduce novel combinations of CIB1 depletion with docetaxel and TRAIL that result in significantly enhanced cell death via death receptor-mediated apoptosis and paraptosis, a non-apoptotic mode of cell death in TNBC cells. Additionally, the combination treatments activated both cell death mechanisms in docetaxel-resistant TNBC cells. In contrast, CIB1 depletion alone or with either docetaxel or TRAIL spared normal breast epithelial cells from both apoptotic and paraptotic cell death. The results collectively demonstrate investigation of cell death mechanisms for future design of safe, efficacious combination therapies for TNBC. CIB1 regulates PI3K-AKT and MEK-ERK oncogenic pathways that drive TNBC tumorigenesis. However, the signaling cascades that connect CIB1 to these oncogenic pathways are not fully understood. To further understand the signaling network surrounding CIB1, we collaborated with the laboratory of Dr. Xian Chen to profile CIB1-depleted TNBC cells via phosphoproteomic analysis. Using TNBC cells that are sensitive (MDA-468) and insensitive (MDA-231) to CIB1 depletion, our goal was to uncover additional CIB1-dependent signaling pathways. The analysis generally revealed significant differences in protein activities upon CIB1 depletion in MDA-468 compared to the insensitive MDA-231 cells. More specifically, we found increased SHIP2 and PP2A activities in CIB1 depleted MDA-468, later validated by phosphatase assay. While it is unclear as to whether CIB1 depletion-induced increase in PP2A and SHIP2 phosphatase activity is important for regulating AKT and ERK activities, their roles as scaffolding proteins remain to be explored. Taken together, my results further validate CIB1 as a promising target. |
