ORCID ID
Graduation Date
Fall 12-20-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Immunology, Pathology & Infectious Disease
First Advisor
Maher Abdalla
Abstract
Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, emphasizing the critical need for innovative therapeutic strategies. Conventional treatments, including chemotherapy, radiotherapy, and hormonal therapy, often face limitations due to resistance mechanisms that diminishes their effectiveness. Targeting the heme degradation pathway through the inhibition of heme oxygenase-1 (HO-1), an inducible enzyme involved in heme catabolism, has emerged as a promising approach to overcoming these challenges. HO-1 plays a pivotal role in PC progression by influencing cell proliferation, apoptosis, angiogenesis, and the tumor microenvironment (TME). Moreover, HO-1 contributes to therapy resistance, affecting the efficacy of standard treatments.
We investigated the multifaceted role of HO-1 in PC, highlighting its involvement in therapy resistance and immune modulation, while evaluating the potential of HO-1 inhibition as a therapeutic strategy. Both In vitro and in vivo experiments demonstrated that targeting HO-1 can potentiate the effects of chemotherapy, particularly docetaxel (Doc). The combination of HO-1 inhibition, using zinc protoporphyrin (ZnPP) or tin protoporphyrin (SnPP), with Doc significantly reduces tumor cell viability under both hypoxic and normoxic conditions. This synergistic effect sensitizes PC cells to Doc-induced apoptosis through interconnected mechanisms, including increased expression of reactive oxygen species (ROS), disruption of the glutathione cycle, and modulation of the Signal Transducer and Activator of Transcription 1 (STAT1) pathway. Additionally, HO-1 inhibition mitigated the epithelial-to-mesenchymal transition (EMT), reducing cell migration and promoting a less invasive phenotype.
In vivo studies further confirm that combining the HO-1 inhibitor (SnPP) with Doc significantly enhances anti-tumor efficacy. This combination treatment reduces Ki67 expression, increases cleaved caspase-3 (CC3) expression, enhances CD4+ and CD8+ T-cell infiltration, and shifts macrophage polarization toward a pro-inflammatory M1 phenotype, indicating a robust immune response against cancer cells.
Additionally, HO-1 inhibition also shows promise in enhancing the response to combined hormonal and radiotherapy. By downregulating androgen receptor (AR) expression and modulating the AKT signaling pathway, HO-1 inhibition increases PC cell radiosensitivity, offering a promising strategy to overcome therapy resistance.
Collectively, these findings highlight the therapeutic potential of HO-1 inhibition in PC. By unraveling the complex roles of HO-1 in tumor biology and therapy resistance, our research paves the way for novel combination therapies that could enhance clinical outcomes for PC patients, particularly in the context of therapy resistance and immune modulation.
Recommended Citation
Salloom, Ramia J., "Therapeutic Effects of Targeting the Heme Degradation Pathway in Prostate Cancer" (2024). Theses & Dissertations. 880.
https://digitalcommons.unmc.edu/etd/880
Comments
2024 Copyright, the authors